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WO2025038785A1 - Sos1 protein degraders, pharmaceutical compositions, and therapeutic applications - Google Patents

Sos1 protein degraders, pharmaceutical compositions, and therapeutic applications Download PDF

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Publication number
WO2025038785A1
WO2025038785A1 PCT/US2024/042366 US2024042366W WO2025038785A1 WO 2025038785 A1 WO2025038785 A1 WO 2025038785A1 US 2024042366 W US2024042366 W US 2024042366W WO 2025038785 A1 WO2025038785 A1 WO 2025038785A1
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mixture
compound
ethyl
methyl
amino
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WO2025038785A9 (en
Inventor
Akinori Okano
Venkat Reddy Mali
Shenlin Huang
Athri D. RATHNAYAKE
Romelo Gibe
Leah M. Fung
Aparajita Hoskote Chourasia
Kyle BEGOVICH
Elena MARTINEZ
Angela SCHOOLMEESTERS
Navin Rajapakse
Arvind Shakya
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BioTheryX Inc
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BioTheryX Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • SOS1 protein degraders and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of an SOSl-mediated disorder, disease, or condition.
  • RAS mutations are found in about 95% of pancreatic ductal adenocarcinomas (PDACs), about 50% of colorectal adenocarcinomas (CRCs), and about 30% of lung adenocarcinomas (LACs).
  • PDACs pancreatic ductal adenocarcinomas
  • CRCs colorectal adenocarcinomas
  • LACs lung adenocarcinomas
  • a RAS protein is a small GTPase encoded by a RAS oncogene. Papke and Der, Science 2017, 355, 1158-63.
  • the RAS protein functions as a molecular switch cycling between the active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)- bound states. Milburn et al., Science 1990, 247, 939-45.
  • the GTP-bound active RAS activates downstream effector pathways, including rat fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated kinase (RAF/MEK/ERK) and phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin kinase (PI3K/AKT/mTOR). Rebocho and Marais, Cancer 397Discov. 2011, 7, 98-9. Oncogenic mutations in RAS proteins impair their ability for GTP hydrolysis, resulting in the accumulation of GTP-bound active RAS and hyperactivation of downstream signaling cascades that lead to uncontrolled cell proliferation and survival. Uras et al., hit. J. Mol. Set. 2020, 21, 4325.
  • the RAS signaling is tightly regulated by guanine nucleotide exchange factor (GEF) proteins, which catalyze the exchange of GDP for GTP, and GTPase-activating proteins (GAPs), which increase the rate of GTP hydrolysis to GDP.
  • GEF guanine nucleotide exchange factor
  • GAPs GTPase-activating proteins
  • Small molecule S0S1 inhibitors have been shown to be effective in downregulating active RAS in tumor cells with wild-type KRAS as well as tumor cells bearing a KRAS mutation. Hillig et al., Proc. Nat. Acad. Set. 2019, 114, 2551-60. By preventing formation of the KRAS-SOS1 complex, the S0S1 inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. Id.
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
  • A is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
  • L is C1-6 alkylene, C7-15 aralkylene, or a linker
  • R 1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
  • R 3 is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R 4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)
  • R 2a and R 2b are each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R 4a and R 4b is independently hydrogen or R 4 ;
  • R e is an E3 ubiquitin ligase binding moiety; each R 1a , R lb , R 1c , and R 1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano,
  • a pharmaceutical composition comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a son of sevenless homolog 1 (S0S1) in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a RAS in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inhibiting the growth of a cell comprising contacting the cell with a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inducing degradation of an S0S1 comprising contacting the S0S1 with a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • subject refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, pig, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject.
  • the subject is a human.
  • treat is meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • prevent are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
  • the terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition.
  • the terms can also refer to reducing adverse effects associated with an active ingredient.
  • the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
  • contacting or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro ex vivo, or in vivo.
  • a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule.
  • a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell.
  • the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.
  • terapéuticaally effective amount or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a biological molecule e.g., a protein, enzyme, RNA, or DNA
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid fdler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • alkyl refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein.
  • Ci-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.”
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., //-propyl and isopropyl), butyl (including all isomeric forms, e.g., //-butyl, isobutyl, ec-butyl, and Ebutyl), pentyl (including all isomeric forms, e.g., //-pentyl, isopentyl, sec-pentyl, neopentyl, and Zc/7-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).
  • alkylene and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally substituted with one or more substituents Q as described herein.
  • C1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30), 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C3-6 alkanediyl groups are also referred as “lower alkanediyl.”
  • alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane- 1 , 1 -diyl and ethane-1,2- diyl), propanediyl (including all isomeric forms, e.g., propane- 1,1 -diyl, propane- 1,2-diyl, and propane-l,3-diyl), butanediyl (including all isomeric forms, e.g, butane- 1,1 -diyl, butane-1,2- diyl, butane- 1,3 -diyl, and butane- 1,4-diyl), pentanediyl (including all isomeric forms, e.g., pent
  • substituted alkanediyl groups include, but are not limited to, -C(O)CH2- -C(O)(CH 2 ) 2 - -C(O)(CH 2 )3-, -C(O)(CH 2 )4- -C(O)(CH 2 )5- -C(O)(CH 2 )6- -C(O)(CH 2 )7-, -C(O)(CH 2 ) 8 -, -C(O)(CH 2 )9-, -C(0)(CH 2 )IO-, -C(O)CH 2 C(O)-, -C(O)(CH 2 ) 2 C(O)-, -C(O)(CH 2 ) 3 C(O)-, -C(O)(CH 2 ) 4 C(O)-, or -C(O)(CH 2 ) 5 C(O)-.
  • heteroalkyl refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N.
  • the heteroalkyl is optionally substituted with one or more substituents Q as described herein.
  • Ci-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (Ci-is), 1 to 10 (Ci-io), or 1 to 6 (Ci-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C 3 -6 heteroalkyl groups are also referred as “lower heteroalkyl.”
  • heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -CH 2 OCH 3 , -NHCH3, -ONHCH3, -NHOCH3, -SCH 3 , -CH2NHCH2CH3, and -NHCH2CH2CH3.
  • substituted heteroalkyl groups include, but are not limited to, -CH 2 NHC(O)CH 3 and -NHC(O)CH 2 CH 3 .
  • heteroalkylene and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N.
  • the heteroalkylene is optionally substituted with one or more substituents Q as described herein.
  • C1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci -20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Cue) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • linear C1-6 and branched C3-6 heteroalkylene groups are also referred as “lower heteroalkylene.”
  • heteroalkylene groups include, but are not limited to, -CH2O-, -(CH 2 ) 2 O-, -(Cfh ⁇ O-, -(CH 2 ) 4 O- -(CH 2 ) 5 O-, -(CH 2 ) 6 O- -(CH 2 ) 7 O-, -(CH 2 )SO-, -(CH 2 ) 9 O-, -(CH 2 )IOO-, -CH2OCH2-, -CH2CH2O-, -(CH 2 CH 2 O) 2 -, -(CH 2 CH 2 O)3-, -(CH 2 CH 2 O) 4 -, -(CH 2 CH 2 O) 5 -, -CH2NH-, -CH2NHCH2-, -CH2CH2NH- -CH2S-, -CH2SCH2-, and
  • substituted heteroalkylene groups include, but are not limited to, -C(O)CH 2 O-, -C(O)(CH 2 ) 2 O- -C(O)(CH 2 ) 3 O- -C(O)(CH 2 ) 4 O- -C(O)(CH 2 ) 5 O- -C(O)(CH 2 ) 6 O-, -C(O)(CH 2 )7O- -C(O)(CH 2 )SO-, -C(O)(CH 2 ) 9 O-
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s).
  • the alkenyl is optionally substituted with one or more substituents Q as described herein.
  • alkenyl embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen- 1-yl, propen-2 -yl, and allyl), and butenyl (including all isomeric forms, e.g., buten- 1-yl, buten-2-yl, buten-3-yl, and 2-buten-l-yl).
  • alkenylene and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s).
  • the alkenediyl is optionally substituted with one or more substituents Q as described herein.
  • alkenediyl embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g., ethene- 1,1- diyl and ethene- 1,2-diyl), propenediyl (including all isomeric forms, e.g., 1 -propene- 1,1 -diyl, 1- propene-l,2-diyl, and 1 -propene- 1,3 -diyl), butenediyl (including all isomeric forms, e.g., 1- butene- 1,1 -diyl, 1 -butene- 1,2-diyl, and 1 -butene- 1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1 -pentene- 1,1 -diyl, l-pentene-l,2-diyl, and 1 -pentene- 1,5 -di
  • heteroalkenylene and “heteroalkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain.
  • the heteroalkenylene is optionally substituted with one or more substituents Q as described herein.
  • heteroalkenylene embraces radicals having a "cis” or “trans ' configuration or a mixture thereof, or alternatively, a “Z” or “£” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art.
  • C2-6 heteroal kenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms.
  • the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms.
  • alkynyl refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carboncarbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein.
  • C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms.
  • ethynyl ethynyl
  • propynyl including all isomeric forms, e.g., 1-propynyl (-OCCH3) and propargyl (-CH2
  • alkynylene and alkynediyl are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s).
  • An alkynylene group does not contain a carbon-carbon double bond.
  • the alkynediyl is optionally substituted with one or more substituents Q as described herein.
  • C2-6 alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4- e) carbon atoms.
  • alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1 -propyne- 1,3 -diyl and l-propyne-3,3-diyl), butynediyl (including all isomeric forms, e.g., l-butyne-l,3-diyl, 1 -butyne- 1,4-diyl, and 2- butyne- 1,1 -diyl), pentynediyl (including all isomeric forms, e.g., l-pentyne-l,3-diyl, 1-pentyne- 1,4-diyl, and 2-pentyne- 1,1 -diyl), and hexynediyl (including all isomeric forms, e.g., 1-
  • heteroalkynylene and “heteroalkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s), and which contains one or more heteroatoms in its main chain, each independently selected from O, S, and N.
  • a heteroalkynylene group does not contain a carbon-carbon double bond.
  • the heteroalkynylene is optionally substituted with one or more substituents Q as described herein.
  • C2-6 heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms.
  • the heteroalkynylene is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- 6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms.
  • heteroalkynylene groups include, but are not limited to, -C ⁇ CCIEO-, -C ⁇ CCFFS-. or OCCH2NH .
  • cycloalkyl refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein.
  • the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group.
  • the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms.
  • the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic.
  • the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[l. l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.
  • cycloalkylene and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein.
  • cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups.
  • the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms.
  • cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane- 1,1 -diyl and cyclopropane- 1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane- 1, 1 -diyl, cyclobutane- 1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane- 1,1 -diyl, cyclopentane- 1,2-diyl, and cyclopentane- 1,3 -diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane-l,l-diy
  • aryl refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-is), or from 6 to 10 (C6-io) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl.
  • the aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).
  • the aryl is monocyclic.
  • the aryl is bicyclic.
  • the aryl is tricyclic.
  • the aryl is polycyclic.
  • the aryl is optionally substituted with one or more substituents Q as described herein.
  • arylene and “arenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic hydrocarbon ring.
  • the arylene has from 6 to 20 (C6-20), from 6 to 15 (C6-is), or from 6 to 10 (C6-io) ring atoms.
  • arylene groups include, but are not limited to, phenylene (including all isomeric forms, e.g., phen- 1,2-diyl, phen-l,3-diyl, and phen-l,4-diyl), naphthylene (including all isomeric forms, e.g., naphth- 1,2-diyl, naphth- 1,3 -diyl, and naphth- 1,8-diyl), fluorenylene (including all isomeric forms, e.g., fluoren-l,2-diyl, fluoren- 1,3 -diyl, and fluoren- 1,8-diyl), azulenylene (including all isomeric forms, e.g., azulen- 1,2-diyl, azulen- 1,3 -diyl, and azulen-1,8- diyl), anthrylene (including all isomeric forms, e
  • Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth- 1,2-diyl and dihydronaphth- 1 ,8-diyl), indenylene (including all isomeric forms, e.g., inden- 1,2-diyl, inden- 1,5-diyl, and inden-l,7-diyl), indanylene (including all isomeric forms, e.g., indan- 1,2-diyl, indan- 1,5 -diyl, and indan- 1 ,7-diyl), or tetrahydronaphthylene (tetralinyl ene) (including all isomeric forms, e.g., tetrahydronaphth- 1
  • aralkyl or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms.
  • aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2- phenylethyl), and phenylpropyl (including all isomeric forms, e.g, 1 -phenylpropyl, 2- phenylpropyl, and 3 -phenylpropyl).
  • the aralkyl is optionally substituted with one or more substituents Q as described herein.
  • aralkylene or “arylalkylene” refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms.
  • aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethdiyl), phenylethylene (including all isomeric forms, e.g., 2-phenyl-ethan- 1,1 -diyl and 2-phenyl-ethan-l,2-diyl), and phenyl propylene (including all isomeric forms, e.g., 3-phenyl- propan- 1,1 -diyl, 3-phenyl-propan-l,2-diyl, and 3-phenyl-propan-l,3-diyl).
  • the aralkylene is optionally substituted with one or more substituents Q as described herein.
  • heteroaryl refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring.
  • heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring.
  • Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • the heteroaryl is monocyclic.
  • heteroaryl groups examples include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl.
  • the heteroaryl is bicyclic.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-Z>]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-/>]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-/>]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-rz]pyridinyl, imidazo[4,5- Z>]pyridinyl, and imidazo[4,5-c]pyridinyl,
  • the heteroaryl is tricyclic.
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7- phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.
  • the heteroaryl is optionally substituted with one or more substituents Q as described herein.
  • heteroarylene and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N.
  • heteroarylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring the heteroarylene group is not bonded to the rest of a molecule via its nonaromatic heterocyclic ring.
  • Each ring of a heteroarylene group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom.
  • the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.
  • Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrrol diyl, thiadiazoldiyl, thiazoldiyl, thiendiyl, tetrazol diyl, triazinediyl, and triazol diyl.
  • bicyclic heteroarylene groups include, but are not limited to, benzofurandiyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadiazoldiyl, benzothiazoldiyl, benzothiendiyl, benzotriazoldiyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g., furo[2,3-Z?]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2-/>]pyridindiyl, furo[3,2-c]- pyridindiyl, furo[3,4-Z>]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g., imidazo[l,2-rz]pyri)
  • tricyclic heteroarylene groups include, but are not limited to, acridindiyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5-phenanthrolindiyl, 1,6- phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl.
  • heteroarylene is optionally substituted with one or more substituents Q as described herein.
  • heterocyclyl refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one nonaromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms.
  • heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring.
  • the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodi oxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., l,4-dihydrobenzo[ ⁇ 7][l,3]oxazinyl, 3,4-dihydrobenzo[c][l,2]-oxazinyl, and 3,4-dihydrobenzo[ ][l,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydro
  • heterocyclylene refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms.
  • the heterocyclylene group For a heterocyclylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclylene group has at least one bond to the rest of a molecule via its nonaromatic heterocyclic ring.
  • the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms.
  • the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quatemized, and some rings may be partially or fully saturated, or aromatic.
  • the heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclylene groups include, but are not limited to, azepindiyl, benzodi oxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.
  • halogen refers to fluoro, chloro, bromo, and/or iodo.
  • each Q a is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR C , -OC(O)NR f
  • optically active and ’’enantiomerically active refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%.
  • an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
  • an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
  • the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the compound, R and S.
  • isotopically enriched refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon- 11 ( U C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 13 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-
  • an isotopically enriched compound is in a stable form, that is, non-radioactive.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon- 12 ( 12 C), carbon- 13 ( 13 C), nitrogen- 14 ( 14 N), nitrogen- 15 ( 15 N), oxygen- 16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur- 33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 C1), chlorine-37 ( 37 C1), bromine-79 ( 79 Br), bromine-81 ( 81 Br), and iodine-127 ( 127 I).
  • an isotopically enriched compound is in an unstable form, that is, radioactive.
  • an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( U C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 C1), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I), and iodine-131 ( 131 I).
  • any hydrogen can be 2 H, as example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, or any oxygen can be 18 O, as example, where feasible according to the judgment of one of ordinary skill in the art.
  • isotopic enrichment refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope e.g., 1 H for protium or hydrogen-1) of the element.
  • a less prevalent isotope e.g., D for deuterium or hydrogen-2
  • a more prevalent isotope e.g., 1 H for protium or hydrogen-1
  • isotopic enrichment factor refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.
  • hydrogen refers to the composition of naturally occurring hydrogen isotopes, which include protium ( 1 H), deuterium ( 2 H or D), and tritium ( 3 H), in their natural abundances.
  • Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%.
  • Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.
  • deuterium enrichment refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).
  • carbon or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon- 12 ( 12 C) and carbon- 13 ( 13 C) in their natural abundances.
  • Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%.
  • Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.
  • carbon-13 enrichment or “ 13 C enrichment” refers to the percentage of incorporation of carbon- 13 at a given position in a molecule in the place of carbon.
  • carbon- 13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon- 13 at the specified position. Because the naturally occurring distribution of carbon- 13 is about 1.11% on average, carbon- 13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average.
  • when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
  • substantially pure and substantially homogeneous mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • substantially pure or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods.
  • a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound.
  • a deuterated compound that has an atom at a particular position designated as deuterium a compound that contains a protium at the same position is an impurity.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, //-propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable.
  • the complex or aggregate is in a crystalline form.
  • the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate.
  • hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
  • a divalent group described herein no orientation is implied by the direction in which the divalent group is presented.
  • the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.
  • an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a diastereomer,
  • a compound of Formula (I) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
  • A is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
  • L is C1-6 alkylene, C7-15 aralkylene, or a linker
  • R 1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
  • R 3 is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R 4 is independently (i) deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)
  • R 2a and R 2b are each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R 4a and R 4b is independently hydrogen or R 4 ;
  • R e is an E3 ubiquitin ligase binding moiety; each R 1a , R lb , R 1c , and R 1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano,
  • A is C3-10 cycloalkylene, optionally substituted with one or more substituents Q.
  • A is monocyclic C3-10 cycloalkylene, optionally substituted with one or more substituents Q.
  • A is bicyclic C4-10 cycloalkylene, optionally substituted with one or more substituents Q.
  • A is bridged, fused, or spiro C4-10 cycloalkylene, each optionally substituted with one or more substituents Q.
  • A is C6-14 arylene, optionally substituted with one or more substituents Q.
  • A is phendiyl, optionally substituted with one or more substituents Q.
  • A is phendiyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently halo, Ci-6 alkyl, or Ci-6 heteroalkyl.
  • A is phendiyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently fluoro, chloro, or methyl.
  • A is phen-l,2-diyl, phen-l,3-diyl, or phen-l,4-diyl, each optionally substituted with one or more substituents Q.
  • A is phen- 1,3 -diyl, optionally substituted with one or more substituents Q.
  • A is phen-l,3-diyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently halo, Ci-6 alkyl, or Ci-6 heteroalkyl.
  • A is phen- 1,3 -diyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently fluoro, chloro, or methyl.
  • A is phen-l,3-diyl, 2-fluorophen- 1,3 -diyl, 4-fluorophen- 1,3 -diyl, 5 -fluorophen- 1,3 -diyl, 2- chlorophen-l,3-diyl, 4-chlorophen-l,3-diyl, 5-chlorophen-l,3-diyl, 2-methylphen- 1,3 -diyl, 4- methylphen- 1,3 -diyl, or 5-methylphen-l,3-diyl.
  • A is heteroarylene, optionally substituted with one or more substituents Q.
  • A is monocyclic heteroarylene, optionally substituted with one or more substituents Q.
  • A is 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q.
  • A is 5-membered heteroarylene, optionally substituted with one or more substituents Q.
  • A is 6-membered heteroarylene, optionally substituted with one or more substituents Q.
  • A is furandiyl, thiendiyl, or pyridindiyl, each optionally substituted with one or more substituents Q.
  • A is furan-2,4-diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, each optionally substituted with one or more substituents Q.
  • A in any one of the formulae described herein, A is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q.
  • A is heterocyclylene, optionally substituted with one or more substituents Q.
  • A is monocyclic heterocyclylene, optionally substituted with one or more substituents Q.
  • A is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q.
  • A is 6-membered heterocyclylene, optionally substituted with one or more substituents Q.
  • A is 1,2-dihydro- pyridindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q.
  • A is l,2-dihydropyridin-l,5-diyl, l,2-dihydropyridin-3,5-diyl, piperidin-l,3-diyl, morpholin-2,4- diyl, or piperazin- 1 ,4-diyl, each optionally substituted with one or more substituents Q.
  • A is l-methyl-2-oxo-l,2- dihydropyri din-3, 5-diyl, 2-oxo-l,2-dihydropyridin-l,5-diyl, 3-fluoropiperidin-l,3-diyl, morpholin-2,4-diyl, or piperazin- 1 ,4-diyl.
  • A is bicyclic heterocyclylene, optionally substituted with one or more substituents Q.
  • A is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q.
  • A is C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q.
  • A is phendiyl, monocyclic heteroarylene, or monocyclic heterocyclylene, each optionally substituted with one or more substituents Q.
  • A is phendiyl, furandiyl, thiendiyl, pyridindiyl, 1,2-dihydropyridindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q.
  • A is phen-l,3-diyl, furan-2,4- diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-3, 5-diyl, l,2-dihydropyridin-3,5- diyl, 1,2-dihydropyridin-l, 5-diyl, morpholin-2,4-diyl, piperazin- 1,4-diyl, or piperi din- 1,3 -diyl, each optionally substituted with one or more substituents Q.
  • A has the structure wherein:
  • U 6 is -C(R 6b ) 2 - or -O-; each R 5 , R 6a , and R 6b is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a
  • a compound of Formula (II) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R 4 , R 2a , R 2b , R e , L, U, V, X, U 3 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (III) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 3 , R 4 , R 6 , R 2a , R 2b , R 6a , R e , L, U, V, X, U 6 , a, and b are each as defined herein.
  • R 3 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is bicyclic C4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one or more substituents Q.
  • R 3 is C6-14 aryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is C6-14 aryl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is C6-14 aryl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R 3 is C6-14 aryl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is C6-14 aryl, substituted with three substituents Q.
  • R 3 is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3 is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methyl- propyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylamino- methylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl.
  • R 3 is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, nitro, methyl, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R 3 is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, methyl, difluoromethyl, trifluoromethyl, or amino.
  • R 3 is phenyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is phenyl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is phenyl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R 3 is phenyl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is phenyl, substituted with three substituents Q.
  • R 3 is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3 is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2- hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl-phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl.
  • R 3 is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, nitro, methyl, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R 3 is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, methyl, difluoromethyl, trifluoromethyl, or amino.
  • R 3 is 3- cyanophenyl, 3-bromophenyl, 3 -methylphenyl, 3 -difluorom ethylphenyl, 3 -trifluorom ethylphenyl, 3-(l-cyano-l,l-difhioromethyl)phenyl, 3-(l,l-difhioro-2-hydroxyethyl)phenyl, 3-(2- aminomethylphenyl)phenyl, 3-cyano-5-fluorophenyl, 3-cyano-2-methylphenyl, 3-cyano-5- methylphenyl, 3-cyano-2-trifluoromethylphenyl, 3-cyano-5-hydroxyphenyl, 3 -cyano-2-m ethoxyphenyl, 3-nitro-5-trifluoromethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2-chloro-3
  • R 3 is 3-difluoromethyl-2-fluorophenyl, 3-difluoromethyl-2-methyl- phenyl, 3-cyano-2-methylphenyl, 3-nitro-5-trifluoromethylphenyl, 3-fluoro-2-methylphenyl, 2- methyl-3 -trifluoromethylphenyl, or 3-amino-5-trifluoromethylphenyl.
  • R 3 is 3-difluoromethyl-2-fluorophenyl, 3-difluoro- methyl-2-methylphenyl, 3-cyano-2-methylphenyl, 3-fluoro-2-methylphenyl, 2-methyl-3- trifluoromethylphenyl, or 3 -amino-5-trifluorom ethylphenyl.
  • R 3 is bicyclic Cs-14 aryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is bicyclic Cs-i4 aryl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is bicyclic Cs-14 aryl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R 3 is bicyclic Cs-14 aryl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is bicyclic Cs-14 aryl, substituted with three substituents Q.
  • R 3 is 5,6- or 6,6-fused C9-14 aryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is 2,3-dihydroindenyl or naphthyl, each optionally substituted with one, two, or three substituents Q.
  • R 3 is 2,3-dihydroindenyl or naphthyl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano, halo, or nitro; (ii) C1-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1 b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3 is 2,3-dihydroinden-4-yl, 2,3-dihydroinden-5-yl, naphth-l-yl, or naphth-2-yl, each optionally substituted with one, two, or three substituents, each of which is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2- hydroxy ethyl, l,l-difluoro-2-hydroxy-2-m ethylpropyl, methylaminomethyl, 2-aminom ethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy
  • R 3 is l,l-difluoro-2,3-dihydroinden-4-yl or naphth-l-yl.
  • R 3 is heteroaryl, optionally substituted with one, two, or three substituents Q.
  • R 3 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q.
  • R 3 is 5- or 6-membered heteroaryl, each optionally substituted with one, two, or three substituents Q.
  • R 3 is thienyl or pyridinyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is thien-2-yl or thien-3-yl, each independently substituted with C6-14 aryl or heteroaryl, where the aryl and heteroaryl are each optionally further substituted with one, two, or three substituents Q a .
  • R 3 is thienyl or pyridinyl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3 is thien- 2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoro- methyl, 1,1 -difl uoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethylphenyl, 2- dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl
  • R 3 is thien-2-yl, 5-(2-hydroxy- methylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)- thien-2-yl, or 5-(2-(2-aminoethyl)phenyl)thien-2-yl.
  • R 3 is bicyclic heteroaryl, optionally substituted with one, two, or three substituents Q.
  • R 3 is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is 5,5-fused heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is 5,6-fused heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is 6,6-fused heteroaryl, optionally substituted with one, two, or three substituents Q.
  • R 3 is thien- 2-yl, 5-(2-hydroxymethyl-phenyl)thien-2-yl, 5-(2-amino-methylphenyl)thien-2-yl, 4-(2-methyl- aminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)-phenyl)thien-2-yl, or 5-(6,7-dihydro- py rrol o [ 1 ,2-a] imi dazol -3 -y 1 )thi en-2-y 1.
  • R 3 is heterocyclyl, optionally substituted with one, two, or three substituents Q.
  • R 3 is monocyclic heterocyclyl, optionally substituted with one, two, or three substituents Q.
  • R 3 is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q.
  • R 3 is bicyclic heterocyclyl, optionally substituted with one, two, or three substituents Q.
  • R 3 is bridged, fused, or spiro heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is 2,3- dihydrobenzofuranyl, optionally substituted with one, two, or three substituents Q.
  • R 3 is C6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3 is phenyl or monocyclic heteroaryl, each optionally substituted with one or more substituents Q.
  • R 3 is 3- cyanophenyl, 3 -bromophenyl, 3 -methylphenyl, 3 -difluoromethylphenyl, 3 -trifluorom ethylphenyl, 3-(l,l-difhioroethyl)phenyl, 3-(l-cyano-l-fluoromethyl)phenyl, 3-(l-cyano-l,l-difluoro- methyl)phenyl, 3-(l,l-difluoro-2-hydroxyethyl)phenyl, 3-(2-aminomethylphenyl)phenyl, 3- cyano-5-fluorophenyl, 3-cyano-2-methylphenyl, 3-cyano-5-methylphenyl, 3-cyano-2-trifluoro- methylphenyl, 3-cyano-5-hydroxyphenyl, 3-cyano-2-methoxyphenyl, 3 -nitro-5
  • R 2b is hydrogen. In certain embodiments, in any one of the formulae described herein, R 2b is deuterium. In certain embodiments, in any one of the formulae described herein, R 2b is halo. In certain embodiments, in any one of the formulae described herein, R 2b is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2b is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2b is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q.
  • R 2b is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2b is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2b is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2b is C6-14 aryl, optionally substituted with one or more substituents Q.
  • R 2b is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2b is heterocyclyl, optionally substituted with one or more substituents Q.
  • a compound of Formula (IV) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
  • R 3a , R 3b , R 3C , R 3d , and R 3e are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1 a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1
  • R 1 , R 4 , R 1a , R lb , R 1c , R 1d , R 2a , R e , L, U, V, X, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (V) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 6 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 6a , R e , L, U, V, X, U 6 , a, and b are each as defined herein.
  • a compound of Formula (VI) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R e , L, U, V, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (VII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 6 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 6a , R e , L, U, V, U 6 , a, and b are each as defined herein.
  • a compound of Formula (VIIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (VIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (IXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 6 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R 6a , R e , L, U 6 , a, and b are each as defined herein.
  • a compound of Formula (XA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 6 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R 6a , R e , L, U 6 , a, and b are each as defined herein.
  • a compound of Formula (XIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 6 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R 6a , R e , L, U 6 , a, and b are each as defined herein.
  • a compound of Formula (IXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 6 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R 6a , R e , L, U 6 , a, and b are each as defined herein.
  • a compound of Formula (XB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 6 , R 2a , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R 6a , R e , L, U 6 , a, and b are each as defined herein.
  • a compound of Formula (XIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 6 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R 6a , R e , L, U 6 , a, and b are each as defined herein.
  • R e is a moiety of a cereblon (CRBN) E3 ligand.
  • R e is a moiety having the structure of Formula (El): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein:
  • a e is a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
  • Z is -CH2- or -C(O)-;
  • Z 1 is a bond;
  • R e1 is hydrogen, deuterium, halo, or C1-6 alkyl
  • R e2 is hydrogen or C1-6 alkyl; each R e3 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R
  • R e is a moiety having the structure of Formula (Eli): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0, 1, 2, or 3; and A e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R c is a moiety having the structure of Formula (EIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EIV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EVI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • EVI Formula
  • R e is a moiety having the structure of Formula (EVII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EVIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EIX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EXI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EXII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and A e , R e1 , R e2 , R e3 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EXIII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EXIV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e4 , Z, and m are each as defined herein.
  • R e is a moiety having the structure of Formula (EXV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein:
  • X c is C(R cl ) or N;
  • R e5 is (i) hydrogen; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; or (iii) -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1 a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c
  • a e , R 1a , R lb , R 1c , R 1d , R e1 , R e2 , R e3 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXVI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e3 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXVII): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e2 , R e3 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXVIII):
  • R e is a moiety having the structure of Formula (EXIX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e3 , R e5 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXX): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e3 , R w , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXI): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e3 , R e? , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXII): (EXXII) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e2 , R e3 , X e , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXIII):
  • R e is a moiety having the structure of Formula (EXXIV):
  • R e is a moiety having the structure of Formula (EXXV): or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A c , R cl , R c2 , R c3 , m, and n are each as defined herein.
  • R e is a moiety having the structure of Formula (EXXVI):
  • R e is a moiety having the structure of Formula (EXXVII):
  • R e is a moiety having the structure of Formula (EXXII):
  • R e is a moiety having the structure of Formula (El), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (Eli), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R c is a moiety having the structure of Formula (EXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula (EXXVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e and R e4 are each as defined herein.
  • R e is a moiety having the structure of Formula El, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of:
  • R e is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , and R e4 are each as defined herein.
  • R e is a moiety having the structure of Formula E3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E5, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E6, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E7, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E8, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of:
  • R e is a moiety having the structure of: or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein A e , R e1 , R e3 , and n are each as defined herein.
  • R e is a moiety having the structure of Formula E9, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E10, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula Ell, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula Ell, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E13, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of Formula E14, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
  • R e is a moiety having the structure of:
  • R e is a moiety having the structure of:
  • a compound of Formula (XIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XIIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XIVA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e2 , R e4 , R e5 , A e , L, U 5 , V 5 , X 5 , Z 5 , X e , and a are each as defined herein.
  • a compound of Formula (XVIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 3 , and a are each as defined herein.
  • a compound of Formula (XVIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XIVB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3c , R 3d , R 3c , R 4a , R c2 , R c4 , R c5 , A c , L, U 5 , V 5 , X 5 , Z 5 , X c , and a are each as defined herein.
  • a compound of Formula (XVB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e5 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XVIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e5 , A e , L, IF, V 2 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XVIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e5 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XVIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3c , R 3d , R 3e , R 4a , R e2 , R e4 , R e5 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XIXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e2 , R e4 , R e5 , A e , L, U 5 , V 5 , X 5 , Z 5 , X e , and a are each as defined herein.
  • a compound of Formula (XXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 3 , and a are each as defined herein.
  • a compound of Formula (XXIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3C , R 4a , R cl , R c2 , R c4 , R c5 , A c , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XXIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 3 , and a are each as defined herein.
  • a compound of Formula (XIXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e2 , R e4 , R e5 , A e , L, U 5 , V 5 , X 5 , Z 5 , X e , and a are each as defined herein.
  • a compound of Formula (XXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e5 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XXIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e4 , R e5 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XXIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e2 , R e5 , R e6 , A e , L, U 5 , V 5 , X 5 , Z 5 , and a are each as defined herein.
  • a compound of Formula (XXIVA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e2 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 5 , X e , a, and n are each as defined herein.
  • a compound of Formula (XXV A) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 3 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • a compound of Formula (XXVIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • XXVIIA or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 3 , V 3 , X 5 , Z 5 , a, and n are each as defined herein.
  • a compound of Formula (XXVIII A) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e2 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 3 , a, and n are each as defined herein.
  • a compound of Formula (XXIVB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e2 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 3 , X e , a, and n are each as defined herein.
  • a compound of Formula (XXVIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • XXVIIB or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • a compound of Formula (XXVIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e2 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 5 , a, and n are each as defined herein.
  • a compound of Formula (XXIXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e2 , R e3 , A e , L, U 5 , V 5 , X ? , Z 5 , X e , a, and n are each as defined herein.
  • a compound of Formula (XXXA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • a compound of Formula (XXXIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 3 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • XXXIIA or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • a compound of Formula (XXXIIIA) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e2 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 3 , a, and n are each as defined herein.
  • a compound of Formula (XXIXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e2 , R e3 , A e , L, U 5 , V 5 , X 3 , Z 5 , X e , a, and n are each as defined herein.
  • a compound of Formula (XXXB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • a compound of Formula (XXXIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • XXXIIB or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3e , R 3d , R 3e , R 4a , R e1 , R e2 , R e3 , A e , L, U 5 , V 5 , X 5 , Z 5 , a, and n are each as defined herein.
  • a compound of Formula (XXXIIIB) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 1 , R 4 , R 2a , R 3a , R 3b , R 3C , R 3d , R 3e , R 4a , R e2 , R e3 , A e , L, L , V 2 , X 5 , Z 5 , a, and n are each as defined herein.
  • R 1 is hydrogen. In certain embodiments, in any one of the formulae described herein, R 1 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is methyl. In certain embodiments, in any one of the formulae described herein, R 1 is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 1 is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is C7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 1 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 1 is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 4 is deuterium. In certain embodiments, in any one of the formulae described herein, R 4 is cyano. In certain embodiments, in any one of the formulae described herein, R 4 is halo. In certain embodiments, in any one of the formulae described herein, each R 4 is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 4 is nitro. In certain embodiments, in any one of the formulae described herein, each R 4 is independently Ci-6 alkyl, optionally substituted with one or more substituents Q.
  • R 4 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 4 is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 4 is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 4 is independently C2-6 alkynyl, optionally substituted with one or more substituents Q.
  • each R 4 is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 4 is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 4 is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 4 is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 4 is independently heterocyclyl, optionally substituted with one or more substituents Q.
  • each R 4 is independently -C(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -C(O)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -C(O)SR 1a , wherein R 1a is as defined herein.
  • each R 4 is independently -C(NR 1 a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -C(S)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -C(S)OR 1a , wherein R 1a is independently as defined herein.
  • each R 4 is independently -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OC(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OC(O)OR 1a , wherein R 1a is independently as defined herein.
  • each R 4 is independently -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OC(O)SR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 4 is independently -OC(S)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OC(S)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OS(O)R 1a , wherein R 1a is independently as defined herein.
  • each R 4 is independently -OS(O)2R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R 4 is independently -NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -NR 1 a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • each R 4 is independently -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -NR 1a C(NR 1 d )NR 1 b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • each R 4 is independently -NR 1a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -NR 1 a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 4 is independently -NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -NR 1 a S(O)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 4 is independently -NR 1a S(0)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -SR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -S(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -S(O)2R 1a , wherein R 1a is independently as defined herein.
  • each R 4 is independently -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 4 is independently -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 5 is hydrogen. In certain embodiments, in any one of the formulae described herein, R 5 is deuterium. In certain embodiments, in any one of the formulae described herein, R ? is cyano. In certain embodiments, in any one of the formulae described herein, each R is independently halo. In certain embodiments, in any one of the formulae described herein, each R 5 is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 5 is fluoro. In certain embodiments, in any one of the formulae described herein, R 5 is nitro.
  • each R 5 is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 5 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 5 is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 5 is independently C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • each R 5 is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 5 is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 5 is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 5 is independently C7-15 aralkyl, optionally substituted with one or more substituents Q.
  • each R 5 is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 5 is independently heterocyclyl, optionally substituted with one or more substituents Q.
  • each R 5 is independently -C(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -C(O)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 3 is independently -C(O)SR 1a , wherein R 1a is independently as defined herein.
  • each R 5 is independently -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 3 is independently -C(S)R 1a , wherein R 1a is independently as defined herein.
  • each R 5 is independently -C(S)OR 1a , wherein R 1a is independently as defined herein.
  • each R 5 is independently -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R 5 is independently -OR 1a , wherein R 1a is independently as defined herein.
  • each R 3 is independently -OC(O)R 1a , wherein R 1a is independently as defined herein.
  • each R 5 is independently -OC(O)OR 1a , wherein R 1a is independently as defined herein.
  • each R 5 is independently -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -OC(O)SR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 5 is independently -OC(S)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -OC(S)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -OS(O)R 1a , wherein R 1a is independently as defined herein.
  • each R 5 is independently -OS(O)2R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R 5 is independently -NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R 3 is independently -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • each R 5 is independently -NR 1 a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • each R 5 is independently -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -NR 1 a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -NR 1 a C(NR 1 d )NR 1b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • each R 5 is independently -NR 1a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -NR 1 a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R is independently -NR 1 a C(S)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 5 is independently -NR 1 a S(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • each R ? is independently -NR 1 a S(0)2R 1d , wherein R 1a and R 1d are each as defined herein.
  • each R 5 is independently -NR 1 a S(O)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 5 is independently -NR 1a S(O)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -SR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -S(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -S(O)2R 1a , wherein R 1a is independently as defined herein.
  • each R 5 is independently -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 5 is independently -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6 is deuterium. In certain embodiments, in any one of the formulae described herein, R 6 is cyano. In certain embodiments, in any one of the formulae described herein, each R 6 is independently halo. In certain embodiments, in any one of the formulae described herein, each R 6 is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 6 is fluoro. In certain embodiments, in any one of the formulae described herein, R 6 is nitro. In certain embodiments, in any one of the formulae described herein, each R 6 is independently Ci-6 alkyl, optionally substituted with one or more substituents Q.
  • R 6 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 6 is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 6 is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 6 is independently C2-6 alkynyl, optionally substituted with one or more substituents Q.
  • each R 6 is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 6 is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 6 is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 6 is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R 6 is independently heterocyclyl, optionally substituted with one or more substituents Q.
  • each R 6 is independently -C(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -C(O)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -C(O)SR 1a , wherein R 1a is independently as defined herein.
  • each R 6 is independently -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -C(S)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -C(S)OR 1a , wherein R 1a is independently as defined herein.
  • each R 6 is independently -C(S)NR 1 b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OC(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OC(O)OR 1a , wherein R 1a is independently as defined herein.
  • each R 6 is independently -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OC(O)SR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 6 is independently -OC(S)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OC(S)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OS(O)R 1a , wherein R 1a is independently as defined herein.
  • each R 6 is independently -OS(O)2R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R 6 is independently -NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • each R 6 is independently -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -NR 1 a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -NR 1 a C(NR 1 d )NR 1b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • each R 6 is independently -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -NR 1 a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -NR 1 a C(S)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 6 is independently -NR 1 a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -NR 1 a S(0)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -NR 1 a S(O)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R 6 is independently -NR 1a S(O)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -SR 1a , wherein R ,a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -S(O)R 1a , wherein R 1a is independently as defined herein.
  • each R 6 is independently -S(O)2R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R 6 is independently -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 2a is hydrogen. In certain embodiments, in any one of the formulae described herein, R 2a is deuterium. In certain embodiments, in any one of the formulae described herein, R 2a is halo. In certain embodiments, in any one of the formulae described herein, R 2a is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2a is methyl.
  • R 2a is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2a is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q.
  • R 2a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2a is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 2a is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 3a is hydrogen. In certain embodiments, in any one of the formulae described herein, R 3a is deuterium. In certain embodiments, in any one of the formulae described herein, R 3a is cyano. In certain embodiments, in any one of the formulae described herein, R 3a is halo. In certain embodiments, in any one of the formulae described herein, R 3a is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 3a is fluoro. In certain embodiments, in any one of the formulae described herein, R 3a is nitro.
  • R 3a is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3a is methyl. In certain embodiments, in any one of the formulae described herein, R 3a is C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3a is C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 3a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3a is C7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 3a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3a is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 3a is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 3a is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3a is -C(S)R 1a , wherein R 1a is as defined herein.
  • R 3a is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R 3a is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3a is -OR 1a , wherein R 1a is as defined herein.
  • R 3a is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 3a is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R 3a is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3a is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 3a is -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3a is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 3a is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3a is -NR 1 b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3a is -NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3a is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3a is -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3a is -NR 1 a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3a is -NR 1 a C(NR 1 d )NR 1 b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R 3a is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3a is -NR 1 a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -NR 1 a S(O)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3a is -NR 1 a S(0)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3a is -SR 1a , wherein R 1a is as defined herein.
  • R 3a is -S(O)R 1a , wherein R 1a is as defined herein.
  • R 3a is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R 3a is -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3a is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3a is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3a is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.
  • R 3a is hydrogen, fluoro, chloro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R 3a is hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R 3a is hydrogen. In certain embodiments, in any one of the formulae described herein, R 3a is fluoro. In certain embodiments, in any one of the formulae described herein, R 3a is methyl.
  • R 3b is hydrogen. In certain embodiments, in any one of the formulae described herein, R 3b is deuterium. In certain embodiments, in any one of the formulae described herein, R 3b is cyano. In certain embodiments, in any one of the formulae described herein, R 3b is halo. In certain embodiments, in any one of the formulae described herein, R 3b is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 3b is fluoro. In certain embodiments, in any one of the formulae described herein, R 3b is nitro.
  • R 3b is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3b is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3b is difluoromethyl, trifluoromethyl, or 1 , 1 -difluoro-2-hydroxy ethyl. In certain embodiments, in any one of the formulae described herein, R 3b is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q.
  • R 3b is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3b is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3b is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3b is C6-14 aryl, optionally substituted with one or more substituents Q.
  • R 3b is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3b is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 3b is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 3b is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3b is -C(S)R 1a , wherein R 1a is as defined herein.
  • R 3b is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R 3b is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3b is -OR 1a , wherein R 1a is as defined herein.
  • R 3b is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 3b is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R 3b is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3b is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 3b is -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3b is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 3b is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3b is -NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3b is amino.
  • R 3b is -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3b is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3b is -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3b is -NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3b is -NR 1 a C(NR 1 d )NR 1 b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R 3b is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -NR 1 a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3b is -NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -NR 1a S(O)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3b is -NR 1 a S(O)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3b is -SR 1a , wherein R 1a is as defined herein.
  • R 3b is -S(O)R 1a , wherein R 1a is as defined herein.
  • R 3b is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R 3b is -S(O)NR 1 b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3b is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3b is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3b is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoro- methyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.
  • R 3b is hydrogen, cyano, fluoro, chloro, bromo, methyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoro- methyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, hydroxyl, amino, or methylsulfonyl.
  • R 3b is cyano, fluoro, nitro, difluoromethyl, trifluoromethyl, or amino.
  • R 3b is cyano, fluoro, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R 3b is cyano. In certain embodiments, in any one of the formulae described herein, R 3b is fluoro. In certain embodiments, in any one of the formulae described herein, R 3b is difluoromethyl. In certain embodiments, in any one of the formulae described herein, R 3b is trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R 3b is amino.
  • R 3c is hydrogen. In certain embodiments, in any one of the formulae described herein, R 3c is deuterium. In certain embodiments, in any one of the formulae described herein, R 3c is cyano. In certain embodiments, in any one of the formulae described herein, R 3c is halo. In certain embodiments, in any one of the formulae described herein, R 3c is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 3c is fluoro. In certain embodiments, in any one of the formulae described herein, R 3c is nitro.
  • R 3c is Ci-6 alkyl, optionally substituted with one or more substituents Q.
  • R 3e is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q.
  • R 3c is C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 3c is C2-6 alkynyl, optionally substituted with one or more substituents Q.
  • R 3c is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3c is C6-i4 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3c is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3c is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3c is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 3e is -C(O)R 1a , wherein R 1a is as defined herein.
  • R 3c is -C(O)OR 1a , wherein R 1a is as defined herein.
  • R 3c is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3c is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 3c is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3C is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R 3c is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3c is -OR 1a , wherein R 1a is as defined herein.
  • R 3c is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 3c is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R 3c is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3c is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 3e is -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3c is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 3c is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3c is -NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3c is -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3e is -NR 1 a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3c is -NR 1 a C(NR 1 d )NR 1b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R 3c is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3c is -NR 1 a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -NR 1 a S(O)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3c is -NR 1 a S(O)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3c is -SR 1a , wherein R 1a is as defined herein.
  • R 3c is -S(O)R 1a , wherein R 1a is as defined herein.
  • R 3c is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R 3c is -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3c is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3e is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3c is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethyl-phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.
  • R 3c is hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R 3c is hydrogen.
  • R 3d is hydrogen. In certain embodiments, in any one of the formulae described herein, R 3d is deuterium. In certain embodiments, in any one of the formulae described herein, R 3d is cyano. In certain embodiments, in any one of the formulae described herein, R 3d is halo. In certain embodiments, in any one of the formulae described herein, R 3d is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 3d is fluoro. In certain embodiments, in any one of the formulae described herein, R 3d is nitro.
  • R 3d is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3d is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3d is difluoromethyl, trifluoromethyl, or 1 , 1 -difluoro-2-hydroxy ethyl. In certain embodiments, in any one of the formulae described herein, R 3d is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q.
  • R 3d is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3d is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3d is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3d is C6-i4 aryl, optionally substituted with one or more substituents Q.
  • R 3d is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3d is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3d is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 3d is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 3d is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R 3d is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3d is -OR 1a , wherein R 1a is as defined herein.
  • R 3d is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 3d is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R 3d is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3d is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 3d is -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3d is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 3d is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3d is -NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is amino. In certain embodiments, in any one of the formulae described herein, R 3d is -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3d is -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3d is -NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3d is -NR 1 a C(NR 1 d )NR 1b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R 3d is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -NR 1 a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3d is -NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -NR 1a S(O)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3d is -NR 1 a S(O)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3d is -SR 1a , wherein R 1a is as defined herein.
  • R 3d is -S(O)R 1a , wherein R 1a is as defined herein.
  • R 3d is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R 3d is -S(O)NR 1 b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3d is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3d is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3d is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.
  • R 3d is hydrogen, cyano, fluoro, chloro, bromo, methyl, di fluoromethyl, trifluoromethyl, l-cyano-1,1 -difluoro- methyl, 1 , 1 -difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, hydroxyl, amino, or methyl sulfonyl.
  • R 3d is cyano, fluoro, nitro, difluoromethyl, trifluoromethyl, or amino.
  • R 3d is cyano, fluoro, difluoromethyl, tri fluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R 3d is cyano. In certain embodiments, in any one of the formulae described herein, R 3d is fluoro. In certain embodiments, in any one of the formulae described herein, R 3d is difluoromethyl. In certain embodiments, in any one of the formulae described herein, R 3d is trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R 3d is amino.
  • R 3e is hydrogen. In certain embodiments, in any one of the formulae described herein, R 3e is deuterium. In certain embodiments, in any one of the formulae described herein, R 3e is cyano. In certain embodiments, in any one of the formulae described herein, R 3c is halo. In certain embodiments, in any one of the formulae described herein, R 3e is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 3e is fluoro. In certain embodiments, in any one of the formulae described herein, R 3e is nitro.
  • R 3e is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3e is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3e is methyl. In certain embodiments, in any one of the formulae described herein, R 3e is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3e is C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 3e is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3e is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3e is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3e is C7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 3e is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 3e is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 3e is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 3e is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3e is -C(S)R 1a , wherein R 1a is as defined herein.
  • R 3c is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R 3e is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3e is -OR 1a , wherein R 1a is as defined herein.
  • R 3e is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 3e is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R 3e is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3e is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 3e is -OC(NR 1a )NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3e is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -OC(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 3e is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3e is -NR 1 b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3e is -NR 1a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3e is -NR 1 a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3e is -NR 1 a C(NR 1 d )NR 1 b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R 3e is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3c is -NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 3e is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3e is -NR 1 a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -NR 1 a S(O)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3e is -NR 1 a S(O)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 3e is -SR 1a , wherein R 1a is as defined herein.
  • R 3e is -S(O)R 1a , wherein R 1a is as defined herein.
  • R 3e is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R 3e is -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 3e is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 3e is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR 1a , -NR 1b R 1c , or -S(O)2R 1a , wherein each R 1a , R lb , and R 1c is as defined herein.
  • R 3e is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.
  • R 3e is hydrogen, fluoro, chloro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R 3e is hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R 3e is hydrogen. In certain embodiments, in any one of the formulae described herein, R 3e is fluoro. In certain embodiments, in any one of the formulae described herein, R 3e is methyl.
  • R 4a is hydrogen. In certain embodiments, in any one of the formulae described herein, R 4a is deuterium. In certain embodiments, in any one of the formulae described herein, R 4a is cyano. In certain embodiments, in any one of the formulae described herein, R 4a is halo. In certain embodiments, in any one of the formulae described herein, R 4a is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 4a is nitro. In certain embodiments, in any one of the formulae described herein, R 4a is Ci-6 alkyl, optionally substituted with one or more substituents Q.
  • R 4a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is C2-6 alkynyl, optionally substituted with one or more substituents Q.
  • R 4a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4a is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 4a is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 4a is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -C(S)R 1a , wherein
  • R 4a is -C(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 4a is -OC(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 4a is -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 4a is -OC(S)R 1a , wherein R 1a is as defined herein.
  • R 4a is -OC(S)OR 1a , wherein R 1a is as defined herein.
  • R 4a is -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 4a is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 4a is -OS(O)2R 1a , wherein R 1a is as defined herein.
  • R 4a is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 4a is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -NR 1 a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is -NR 1 a C(NR 1 d )NR 1b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R 4a is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is -NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -NR 1 a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -NR 1 a S(0)2R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4a is -NR 1 a S(O)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -NR 1 a S(0)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -SR 1a , wherein R 1a is as defined herein.
  • R 4a is -S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -S(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4a is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 4b is hydrogen. In certain embodiments, in any one of the formulae described herein, R 4b is deuterium. In certain embodiments, in any one of the formulae described herein, R 4b is cyano. In certain embodiments, in any one of the formulae described herein, R 4b is halo. In certain embodiments, in any one of the formulae described herein, R 4b is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 4b is nitro. In certain embodiments, in any one of the formulae described herein, R 4b is Ci-6 alkyl, optionally substituted with one or more substituents Q.
  • R 4b is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4b is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4b is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4b is C2-6 alkynyl, optionally substituted with one or more substituents Q.
  • R 4b is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4b is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4b is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 4b is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 4b is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 4b is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 4b is -C(S)R 1a , wherein R 1a is as defined herein.
  • R 4b is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R 4b is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 4b is -OR 1a , wherein R 1a is as defined herein.
  • R 4b is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 4b is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R 4b is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 4b is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 4b is -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 4b is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 4b is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 4b is -NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 4b is -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4b is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4b is -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 4b is -NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 4b is -NR 1 a C(NR 1 d )NR 1b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R 4b is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -NR 1 a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 4b is -NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -NR 1a S(O)NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 4b is -NR 1a S(0)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 4b is -SR 1a , wherein R 1a is as defined herein.
  • R 4b is -S(O)R 1a , wherein R 1a is as defined herein.
  • R 4b is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R 4b is -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 4b is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6a is hydrogen. In certain embodiments, in any one of the formulae described herein, R 6a is deuterium. In certain embodiments, in any one of the formulae described herein, R 6a is cyano. In certain embodiments, in any one of the formulae described herein, R 6a is halo. In certain embodiments, in any one of the formulae described herein, R 6a is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 6a is fluoro. In certain embodiments, in any one of the formulae described herein, R 6a is nitro.
  • R 6a is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6a is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6a is C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 6a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6a is C7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 6a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6a is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 6a is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 6a is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R 6a is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6a is -OR 1a , wherein R 1a is as defined herein.
  • R 6a is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 6a is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R 6a is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6a is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 6a is -OC(NR 1a )NR 1 b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6a is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -OC(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 6a is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6a is -NR 1 b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6a is -NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 6a is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 6a is -NR 1a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6a is -NR 1 a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 6a is -NR 1 a C(NR 1 d )NR 1 b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R 6a is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6a is -NR 1 a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -NR 1 a S(0)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -NR 1 a S(O)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6a is -NR 1 a S(0)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6a is -SR 1a , wherein R 1a is as defined herein.
  • R 6a is -S(O)R 1a , wherein R 1a is as defined herein.
  • R 6a is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R 6a is -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6a is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6b is hydrogen. In certain embodiments, in any one of the formulae described herein, R 6b is deuterium. In certain embodiments, in any one of the formulae described herein, R 6b is cyano. In certain embodiments, in any one of the formulae described herein, R 6b is halo. In certain embodiments, in any one of the formulae described herein, R 6b is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R 6b is fluoro. In certain embodiments, in any one of the formulae described herein, R 6b is nitro.
  • R 6b is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6b is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6b is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6b is C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R 6b is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6b is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6b is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6b is C7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R 6b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R 6b is heterocyclyl, optionally substituted with one or more substituents Q.
  • R 6b is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R 6b is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6b is -C(S)R 1a , wherein R 1a is as defined herein.
  • R 6b is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R 6b is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6b is -OR 1a , wherein R 1a is as defined herein.
  • R 6b is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R 6b is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R 6b is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6b is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R 6b is -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6b is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R 6b is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6b is -NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6b is -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R 6b is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 6b is -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R 6b is -NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein.
  • R 6b is -NR 1 a C(NR 1 d )NR 1b R 1c , wherein R 1a , R 1b , R 1c , and R 1d are each as defined herein.
  • R 6b is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -NR 1 a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6b is -NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -NR 1a S(O)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6b is -NR 1 a S(O)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R 6b is -SR 1a , wherein R 1a is as defined herein.
  • R 6b is -S(O)R 1a , wherein R 1a is as defined herein.
  • R 6b is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R 6b is -S(O)NR 1 b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R 6b is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R e1 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e1 is deuterium. In certain embodiments, in any one of the formulae described herein, R e1 is halo. In certain embodiments, in any one of the formulae described herein, R e1 is fluoro. In certain embodiments, in any one of the formulae described herein, R e1 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e1 is methyl.
  • R e2 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e2 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e2 is (pivaloyloxy )methyl, valyloxymethyl, or ((di-tert- butoxyphosphoryl)oxy)methyl.
  • R e3 is deuterium. In certain embodiments, in any one of the formulae described herein, R e3 is cyano. In certain embodiments, in any one of the formulae described herein, R e3 is independently halo. In certain embodiments, in any one of the formulae described herein, each R e3 is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R e3 is nitro. In certain embodiments, in any one of the formulae described herein, each R e3 is independently Ci-6 alkyl, optionally substituted with one or more substituents Q.
  • R e3 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R e3 is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R e3 is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R e3 is independently C2-6 alkynyl, optionally substituted with one or more substituents Q.
  • each R e3 is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R c3 is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R e3 is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R e3 is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R e3 is independently heterocyclyl, optionally substituted with one or more substituents Q.
  • each R e3 is independently -C(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -C(O)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R e3 is independently -C(O)SR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -C(S)R 1a , wherein R 1a is independently as defined herein.
  • each R e3 is independently -C(S)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -OC(O)R 1a , wherein R 1a is independently as defined herein.
  • each R e3 is independently -OC(O)OR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -OC(O)SR 1a , wherein R 1a is independently as defined herein.
  • each R e3 is independently -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R c3 is independently -OC(S)R 1a , wherein R 1a is independently as defined herein.
  • each R e3 is independently -OC(S)OR 1a , wherein R 1a is independently as defined herein.
  • each R e3 is independently -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R e3 is independently -OS(O)R 1a , wherein R 1a is independently as defined herein.
  • each R e3 is independently -OS(O)2R 1a , wherein R 1a is independently as defined herein.
  • each R e3 is independently -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -OS(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R e3 is independently -NR 1a C(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -NR 1 a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • each R e3 is independently -NR 1a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -NR 1 a C(iNR 1d )NR 1b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein.
  • each R e3 is independently -NR 1 a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -NR 1 a S(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • each R e3 is independently -NR 1 a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein.
  • each R c3 is independently -NR 1 a S(O)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R e3 is independently -NR 1 a S(O)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • each R e3 is independently -SR 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -S(O)R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -S(O)2R 1a , wherein R 1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R e3 is independently -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R e4 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e4 is deuterium. In certain embodiments, in any one of the formulae described herein, R e4 is cyano. In certain embodiments, in any one of the formulae described herein, R e4 is halo. In certain embodiments, in any one of the formulae described herein, R e4 is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R e4 is nitro.
  • R e4 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e4 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e4 is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e4 is C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R e4 is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e4 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e4 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e4 is C?-i5 aralkyl, optionally substituted with one or more substituents Q.
  • R e4 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e4 is heterocyclyl, optionally substituted with one or more substituents Q.
  • R e4 is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R e4 is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R e4 is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R e4 is -OR 1a , wherein R 1a is as defined herein.
  • R e4 is -OC(O)R 1a , wherein R 1a is as defined herein.
  • R e4 is -OC(O)OR 1a , wherein R 1a is as defined herein.
  • R e4 is -OC(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R e4 is -OC(O)SR 1a , wherein R 1a is as defined herein.
  • R e4 is -OC(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R e4 is -OC(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -OC(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -OC(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -OS(O)R 1a , wherein R 1a is as defined herein.
  • R e4 is -OS(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -OS(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -0S(0)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R c4 is -NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R e4 is -NR 1 a C(O)R 1d , wherein R 1a and R 1d are each as defined herein.
  • R e4 is -NR 1a C(O)OR 1d , wherein R 1a and R 1d are each as defined herein.
  • R e4 is -NR 1 a C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -NR 1 a C(O)SR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -NR 1 a C(NR 1 d )NR 1b R 1c , wherein R 1a , R lb , R 1c , and R 1d are each as defined herein.
  • R e4 is -NR 1 a C(S)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -NR 1a C(S)OR 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -NR 1 a C(S)NR 1b R 1c , wherein R 1a , R 1b , and R 1c are each as defined herein.
  • R e4 is -NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -NR 1 a S(0)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -NR 1 a S(O)NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R e4 is -NR 1 a S(0)2NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R e4 is -SR 1a , wherein R 1a is as defined herein.
  • R e4 is -S(O)R 1a , wherein R 1a is as defined herein.
  • R e4 is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R e4 is -S(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e4 is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R e5 is hydrogen. In certain embodiments, in any one of the formulae described herein, R e5 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e5 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e5 is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e5 is C2-6 alkenyl, optionally substituted with one or more substituents Q.
  • R e5 is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e5 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e5 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R e5 is C7-15 aralkyl, optionally substituted with one or more substituents Q.
  • R e3 is heteroaryl, optionally substituted with one or more substituents Q.
  • R e5 is heterocyclyl, optionally substituted with one or more substituents Q.
  • R e5 is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R e5 is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R e5 is -C(O)NR 1b R 1c , wherein R lb and R 1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R e5 is -C(O)SR 1a , wherein R 1a is as defined herein.
  • R e5 is -C(NR 1a )NR 1b R 1c , wherein R 1a , R lb , and R 1c are each as defined herein.
  • R e5 is -C(S)R 1a , wherein R 1a is as defined herein.
  • R e? is -C(S)OR 1a , wherein R 1a is as defined herein.
  • R e5 is -C(S)NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • R e5 is -S(O)R 1a , wherein R 1a is as defined herein.
  • R e5 in any one of the formulae described herein, is -S(O)2R 1a , wherein R 1a is as defined herein.
  • R e? is -S(O)NR 1 b R 1c , wherein R lb and R 1c are each as defined herein.
  • R e5 is -S(O)2NR 1b R 1c , wherein R lb and R 1c are each as defined herein.
  • a e is a bond. In certain embodiments, in any one of the formulae described herein, A e is C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A e is monocyclic C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A e is bicyclic C4-10 cycloalkylene, optionally substituted with one or more substituents Q.
  • a e is bridged, fused, or spiro C4-10 cycloalkylene, each optionally substituted with one or more substituents Q.
  • a e is C6-14 arylene, optionally substituted with one or more substituents Q.
  • a e is heteroarylene, optionally substituted with one or more substituents Q.
  • a e is heterocyclylene, optionally substituted with one or more substituents Q.
  • a e is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A e is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A e is 6- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A e is bicyclic heterocyclylene, optionally substituted with one or more substituents Q.
  • a e is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A e is bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A e is fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A e is spiro heterocyclylene, optionally substituted with one or more substituents Q.
  • a e is piperidindiyl, piperazindiyl, or 8-azabicyclo[3.2.1]octandiyl, each optionally substituted with one or more substituents Q.
  • a e is piperidin-l,4-diyl, piperazin- 1,4-diyl, or 8-azabicyclo- [3.2.1 ]octan-3,8-diyl, each optionally substituted with one or more substituents Q.
  • L is Ci-6 alkylene or C7-14 arylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q.
  • L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl or ethane- 1 ,2-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl. In certain embodiments, in any one of the formulae described herein, L is ethane- 1 ,2-diyl.
  • L is C7-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is monocyclic C7-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is phendiylmethandiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is phen-l,3-diylmethandiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is -C(O)-.
  • L is a linker having the structure of -Z k -(R k -Z k ) z - wherein: each R k is independently C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Z k is independently a bond, -C(O)-, -C(O)O- -C(O)NR 1 b -, -C(O)S- C(NR 1a )NR 1b , C(S) , -C(S)O , C(S)NR 1b , O , OC(O)O , OC(O)NR 1b , OC(O)S ,
  • each R k is independently Ci-6 alkylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each Z k is independently a bond, -C(O)-, -C(O)NR 1b -, -C(NR 1 a )NR 1b -, -O-, -OC(O)NR 1b -, -NR 1 b - -NR 1 a C(O)NR 1b -, -NR 1 a C(NR 1 d )NR 1b -, -NR 1 a S(O)NR 1b -, -NR 1 a S(O) 2 NR 1b -, -S-, -S(O)- -S(O)2-, -S(O)NR 1b -,
  • each R k is independently C1-6 alkylene, C 2 -6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each Z k is independently a bond, -C(O)-, -C(O)NR 1b -, -O-, -OC(O)NR 1 b -, -NR 1 b -, -NR 1a C(O)NR 1b - -NR 1 a C(NR 1 d )NR 1b -, or -S-; and z is an integer of 0, 1, 2, or 3; where each R 1a , R 1b , and R 1d is as defined herein.
  • each R k is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, ethynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, phendiyl, pyrazoldiyl, imidazoldiyl, tetrazoldiyl, pyrimidindiyl, azetidindiyl, 1,3-dioxandiyl, piperazindiyl, piperidindiyl, or 3,9-diazaspiro[5.5]undecanediyl, each optionally substituted with one or more substituents Q; each Z k is independently a bond, -C(O)-, -
  • each R k is independently methanediyl, ethane- 1,2-diyl, propane- 1,3 -diyl, butane- 1,4-diyl, pentane- 1,5-diyl, hexane-l,6-diyl, ethyne- 1,2-diyl, cyclobutane- 1,1 -diyl, cyclobutane-l,3-diyl, cyclopentane- 1,3- diyl, cyclohexane-l,3-diyl, cyclohexane- 1,4-diyl, phen-l,3-diyl, phen- 1,4-diyl, pyrazol- 1,3 -diyl, pyrazol- 1,4-diyl, imidazol-l,4-diyl, 1,2, 3
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CHs)-.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CHs)-.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CH3)-.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CH?)-; and wherein each amino (NH) group is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CHs)-; and wherein each amino
  • (NH) group is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CHa)-; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, -O-, -NH- or -N(CHs)-.
  • L is:
  • each A k is independently a bond, -O-, -NH-, or -N(CHs)-; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CH3)-; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CH3)-.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CHa)-; and wherein each amino group (NH) is optionally substituted with methyl.
  • L is: wherein each A k is independently a bond, -O-, -NH-, or -N(CHs)-.
  • U 6 is -C(R b )2-, wherein each R 6b is as defined herein. In certain embodiments, in any one of the formulae described herein, U 6 is -C(H)(R 6b )-, wherein R 6b is as defined herein. In certain embodiments, in any one of the formulae described herein, U 6 is -C(H2)-. In certain embodiments, in any one of the formulae described herein, U 6 is -O-.
  • X e is C(R e1 ), wherein R e1 is as defined herein. In certain embodiments, in any one of the formulae described herein, X e is N.
  • Z is -Chhin certain embodiments, in any one of the formulae described herein, Z is -C(O)-.
  • a is an integer of 0. In certain embodiments, in any one of the formulae described herein, a is an integer of 1. In certain embodiments, in any one of the formulae described herein, a is an integer of 2.
  • b is an integer of 0. In certain embodiments, in any one of the formulae described herein, b is an integer of 1. In certain embodiments, in any one of the formulae described herein, b is an integer of 2. In certain embodiments, in any one of the formulae described herein, b is an integer of 3. In certain embodiments, in any one of the formulae described herein, b is an integer of 4. In certain embodiments, in any one of the formulae described herein, b is an integer of 5. In certain embodiments, in any one of the formulae described herein, b is an integer of 6.
  • m is an integer of 0. In certain embodiments, in any one of the formulae described herein, m is an integer of 1. In certain embodiments, in any one of the formulae described herein, m is an integer of 2.
  • n is an integer of 0. In certain embodiments, in any one of the formulae described herein, n is an integer of 1 . In certain embodiments, in any one of the formulae described herein, n is an integer of 2. In certain embodiments, in any one of the formulae described herein, n is an integer of 3.
  • n is an integer of 1; and R e3 is (i) halo; or (ii) Ci-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one or more substituents Q.
  • n is an integer of 1; and R e3 is (i) halo; or (ii) C1-6 alkyl or monocyclic C3-10 cycloalkyl, each optionally substituted with one or more substituents Q.
  • n is an integer of 1; and R e3 is fluoro, chloro, methyl, difluoromethyl, trifluorom ethyl, or cyclopropyl. In certain embodiments, in any one of the formulae described herein, n is an integer of 2; and each R e3 is independently (i) halo; or (ii) C1-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one or more substituents Q.
  • n is an integer of 2; and each R e3 is independently (i) halo; or (ii) C1-6 alkyl or monocyclic C3-10 cycloalkyl, each optionally substituted with one or more substituents Q.
  • n is an integer of 2; and each R e3 is independently fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, or cyclopropyl.
  • a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon-14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to, 15 N for nitrogen; 17 O or 18 O for oxygen, and 34 S, 35 S, or 36 S for sulfur.
  • a compound provided herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 50, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000.
  • an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope.
  • the maximum isotopic enrichment factor is different for different isotopes.
  • the maximum isotopic enrichment factor is 6,410 for deuterium and 90 for carbon-13.
  • a compound provided herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about
  • the deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.
  • at least one of the atoms of a compound provided herein, as specified as deuterium-enriched has deuterium enrichment of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
  • a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
  • the compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified.
  • a compound provided herein contains an alkenyl group
  • the compound may exist as one or mixture of geometric cisltrans (or ZIE) isomers.
  • structural isomers are interconvertible
  • the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • a compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers.
  • a compound in its (R) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its ( ) form.
  • Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
  • a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1- 19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011.
  • a pharmaceutically acceptable salt of a compound provided herein is a solvate.
  • a pharmaceutically acceptable salt of a compound provided herein is a hydrate.
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentis
  • Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, A'-m ethyl - glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine,
  • a compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound and is readily convertible into the parent compound in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
  • a pharmaceutical composition comprising a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  • a compound provided herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition provided herein can be formulated in various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration.
  • the pharmaceutical composition can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra, Modified- Release Drug Delivery Technology, 2nd ed.; Rathbone el al, Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.
  • the pharmaceutical composition provided herein is formulated in a dosage form for oral administration. In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration. In still another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for topical administration.
  • the pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form.
  • a unit-dosage form refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art.
  • Each unit-dose contains a predetermined quantity of an active ingredient(s) (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s).
  • an active ingredient(s) e.g., a compound provided herein
  • Examples of a unit-dosage form include, but are not limited to, an ampoule, syringe, and individually packaged tablet and capsule.
  • a unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of a multiple-dosage form include, are not limited to, a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • the pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.
  • oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fdlers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fdlers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500®); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, Ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), VEEGUM®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, cellulose
  • Suitable fdlers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pre-gelatinized starch.
  • the amount of a binder or filler in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical composition provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • C6rtain diluents such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • the amount of a diluent in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cationexchange resins; alginic acid; gums, such as guar gum and VEEGUM® HV; citrus pulp; crosslinked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; crosslinked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pregelatinized starch; clays; and algins.
  • the amount of a disintegrant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical composition provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; and silica or silica gels, such as AEROSIL® 200 and CAB-O-SIL®.
  • the amount of a lubricant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O- SIL®, and asbestos-free talc.
  • Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes.
  • a color lake is a combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN* 80), and triethanolamine oleate.
  • Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, VEEGUM®, acacia, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, and sodium benzoate and alcohol.
  • Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether.
  • Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
  • Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.
  • Suitable organic acids include, but are not limited to, citric and tartaric acid.
  • Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
  • the pharmaceutical composition provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredient(s) from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms can be prepared from an active ingredient(s) in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical composition provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC)
  • DFC dry-filled capsule
  • the soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient(s).
  • the pharmaceutical composition provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups.
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
  • Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient(s), and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350- dimethyl ether, polyethylene gly col-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • a dialkylated mono- or poly-alkylene glycol including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350- dimethyl ether, polyethylene gly col-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • These dosage forms can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as
  • composition provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems.
  • Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • the pharmaceutical composition provided herein for oral administration can be provided as non-efferve scent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the dosage forms described herein.
  • composition provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • the pharmaceutical composition provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • the pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, e.g., Remington: The Science and Practice of Pharmacy, supra.
  • the pharmaceutical composition provided herein for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer’s injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer’s injection.
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and mediumchain triglycerides of coconut oil, and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3 -butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, JV-methyl-2-pyrrolidone, A(A-dimethylacetamide, and dimethyl sulfoxide.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e. ., benzethonium chloride), methyl - and propyl-parabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to, EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including a- cyclodextrin, P-cyclodextrin, hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7-P-cyclodextrin (CAPTISOL®).
  • cyclodextrins including a- cyclodextrin, P-cyclodextrin, hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7-P-cyclodextrin (CAPTISOL®).
  • multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution.
  • the pharmaceutical composition is provided as a sterile dry soluble product, including a lyophilized powder and hypodermic tablet, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical composition is provided as a ready-to-use sterile suspension.
  • the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use.
  • the pharmaceutical composition is provided as a ready-to-use sterile emulsion.
  • compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • the pharmaceutical composition provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical composition provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient(s) in the pharmaceutical composition to diffuse through.
  • Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, poly dimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
  • the pharmaceutical composition provided herein can be administered topically to the skin, orifices, or mucosa.
  • the topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
  • the pharmaceutical composition provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches.
  • the topical formulations of the pharmaceutical composition provided herein can also comprise liposomes, micelles, microspheres, and nanosystems.
  • Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, nonaqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • the pharmaceutical composition can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM and BIOJECTTM.
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water- soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, e.g., Remington: The Science and Practice of Pharmacy, supra. These vehicles are em
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • the pharmaceutical composition provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
  • These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
  • Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
  • Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with an active ingredient(s); and antioxidants as described herein, including bisulfite and sodium metabisulfite.
  • Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and poly acrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
  • compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
  • the pharmaceutical composition provided herein can be administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical composition can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1, 1,2, 3, 3, 3- heptafluoropropane.
  • the pharmaceutical composition can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.
  • Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of an active ingredient(s); a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the pharmaceutical composition provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less.
  • Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the pharmaceutical composition provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
  • composition provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
  • modified release dosage form refers to a dosage form in which the rate or place of release of an active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • the pharmaceutical composition in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s).
  • the pharmaceutical composition provided herein in a modified release dosage form can be fabricated using a matrix-controlled release device known to those skilled in the art. See, e.g., Takada el al. in Encyclopedia of Controlled Drug Delivery, Mathiowitz Ed.; Wiley, 1999; Vol. 2.
  • the pharmaceutical composition provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • an erodible matrix device which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum Ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose
  • the pharmaceutical composition provided herein is formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylenevinyl acetate copolymers, ethyl ene/propylene copolymers, ethyl ene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer,
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • composition provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
  • the pharmaceutical composition provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • an osmotic controlled release device including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.”
  • Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic mono
  • PEO polyethylene oxide
  • PEG polyethylene
  • the other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEMTM EZ can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119.
  • Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, poly vinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • composition in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra, Santus and Baker, J. Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma etal., J. Controlled Release, 2002, 79, 7-27.
  • the pharmaceutical composition provided herein is formulated as an AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers.
  • AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • the pharmaceutical composition provided herein is formulated as an ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical composition provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 pm to about 3 mm, about 50 pm to about 2.5 mm, or from about 100 pm to about 1 mm in diameter.
  • multiparticulates can be made by the processes known to those skilled in the art, including wet-and drygranulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, e.g.
  • excipients or carriers as described herein can be blended with the pharmaceutical composition to aid in processing and forming the multiparticulates.
  • the resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody -based delivery systems.
  • liposome-, resealed erythrocyte-, and antibody -based delivery systems examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751 ; 6,071,495; 6,060,082; 6,048,736; 6,039,975;
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a son of sevenless homolog 1 (SCSI) in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an iso
  • the disorder, disease, or condition mediated by an S0S1 is a proliferative disease.
  • a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a RAS in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically
  • the disorder, disease, or condition mediated by a RAS is a proliferative disease.
  • the RAS is a KRAS.
  • the RAS is a HRAS.
  • the Ras is an NRAS.
  • a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate,
  • the proliferative disease is cancer.
  • the cancer is a solid tumor.
  • the cancer is colon cancer, colorectal cancer, lung cancer, or pancreatic cancer.
  • the cancer is colon cancer.
  • the cancer is colorectal cancer.
  • the cancer is lung cancer.
  • the cancer is non-small cell lung cancer (NSCLC).
  • the cancer is pancreatic cancer.
  • the cancer is an unresectable solid tumor.
  • the cancer is a hematologic malignancy.
  • the cancer is refractory and/or relapsed. In certain embodiments, the cancer is refractory. In certain embodiments, the cancer is relapsed. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is unresectable. In certain embodiments, the cancer is metastatic.
  • the cancer is drug-resistant. In certain embodiment, the cancer is multidrug-resistant. In certain embodiments, the cancer is resistant to a chemotherapy. In certain embodiments, the cancer is resistant to an immunotherapy. In certain embodiments, the cancer is resistant to a standard therapy for the cancer.
  • the cancer bears a KRAS mutation. In certain embodiments, the cancer bears a KRAS mutation at the G12 or G13 position. In certain embodiments, the cancer bears a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the cancer bears a KRAS mutation of G12C. In certain embodiments, the cancer bears a KRAS mutation of G12D. In certain embodiments, the cancer bears a KRAS mutation of G12V. In certain embodiments, the cancer bears a KRAS mutation of G12A. In certain embodiments, the cancer bears a KRAS mutation of G12S. In certain embodiments, the cancer bears a KRAS mutation of G12R. In certain embodiments, the cancer bears a KRAS mutation at the G13 position. In certain embodiments, the cancer bears a KRAS mutation of G13D.
  • the cancer is a solid tumor with a KRAS mutation. In certain embodiments, the cancer is a solid tumor with a KRAS mutation at the G12 or G13 position. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12C. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12D. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12V.
  • the cancer is a solid tumor with a KRAS mutation of G12A. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12S. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12R. In certain embodiments, the cancer is a solid tumor with a KRAS mutation at the G13 position. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G13D.
  • the subject is a mammal. In certain embodiments, the subject is a human.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 60 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 25 mg/kg/day, from about 0.1 to about 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1 to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day. In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 60 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0. 1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 25 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 20 mg/kg/day.
  • the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 15 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 10 mg/kg/day. In still another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 5 mg/kg/day.
  • the administered dose can also be expressed in units other than mg/kg/day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m 2 /day to given either the height or weight of a subject or both. For example, a dose of 1 mg/m 2 /day for a 65 kg human is approximately equal to 58 mg/kg/day.
  • a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intraci sternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e. , transdermal or local) routes of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, CIV, intraci sternal injection or infusion, subcutaneous injection, or implant
  • inhalation nasal, vaginal, rectal, sublingual, or topical (e. , transdermal or local) routes of administration.
  • a compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for each route of administration.
  • a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered parenterally. In yet another embodiment, a compound provided herein is administered intravenously. In yet another embodiment, a compound provided herein is administered intramuscularly. In yet another embodiment, a compound provided herein is administered subcutaneously. In still another embodiment, a compound provided herein is administered topically.
  • a compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time.
  • a compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.
  • a compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID), and three times daily (TID).
  • the administration can be continuous, i.e., every day, or intermittently.
  • the term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals.
  • intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g, daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
  • a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
  • a compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a condition, disorder, or disease described herein.
  • the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder.
  • a first therapy e.g., a prophylactic or therapeutic agent such as a compound provided herein
  • a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject.
  • a second therapy e.g., a prophylactic or therapeutic agent
  • the route of administration of a compound provided herein is independent of the route of administration of a second therapy.
  • a compound provided herein is administered orally.
  • a compound provided herein is administered intravenously.
  • the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • a compound provided herein and a second therapy are administered by the same mode of administration, orally or by IV.
  • a compound provided herein is administered by one mode of administration, e.g., by IV, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally.
  • a method of inhibiting the growth of a cell comprising contacting the cell with a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the cell is a cancerous cell. In certain embodiments, the cell is a human cell. In certain embodiments, the cell is a human cancerous cell.
  • the cell is a cell of colon cancer, colorectal cancer, lung cancer, or pancreatic cancer. In certain embodiments, the cell is a cell of non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the cell is a cancerous cell bearing a KRAS mutation. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation at the G12 or G13 position. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12C. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12D. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12V.
  • the cell is a cancerous cell bearing a KRAS mutation of G12A. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12S. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12R. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation at the G13 position. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G13D.
  • a method of inducing degradation of an S0S1 comprising contacting the S0S1 with a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a compound provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos.
  • Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • kits which, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject.
  • the kit provided herein includes a container and a dosage form of a compound provided herein.
  • Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
  • Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’s injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’s injection
  • water-miscible vehicles including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene
  • g grams
  • mg milligrams
  • mL milliliters
  • p.L microliters
  • mM millimolar
  • pM micromolar
  • mmol millimoles
  • min minute or minutes
  • h hour or hours
  • AcO or OAc acetate
  • Bn benzyl
  • Boc tert-butoxycarbonyl
  • /BuOK potassium ter /-but oxi de
  • DIEA or DIPEA A, A-di isopropyl ethyl amine); Et (ethyl); LDA (lithium diisopropylamide); Ms (mesyl); PMB (/i-m ethoxybenzyl); Pd(dppf)Ch (1,1’- bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex); TFA

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Abstract

Provided herein are SOS1 protein degraders, e.g., a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of an SOS1-mediated disorder, disease, or condition.

Description

SOS1 PROTEIN DEGRADERS, PHARMACEUTICAL COMPOSITIONS , AND THERAPEUTIC APPLICATIONS
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of the priority of U.S Provisional Application Nos. 63/520,067, filed August 16, 2023; and 63/578,285, filed August 23, 2023; the disclosure of each of which is incorporated herein by reference in its entirety.
FIELD
[0002] Provided herein are SOS1 protein degraders and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of an SOSl-mediated disorder, disease, or condition.
BACKGROUND
[0003] The three RAS oncogenes, KRAS, HRAS, and NRAS, are from the most frequently mutated oncogene family in cancer. Milburn et al., Science 1990, 247, 939-45; Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51; Papke and Der, Science 2017, 355, 1158-63. RAS mutations have been detected in up to 30% of all human cancer. Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51. RAS mutations are found in about 95% of pancreatic ductal adenocarcinomas (PDACs), about 50% of colorectal adenocarcinomas (CRCs), and about 30% of lung adenocarcinomas (LACs). Papke and Der, Science 2017, 355, 1158-63. Among the three, KRAS mutations are the most common and alone account for about a million death per year worldwide. Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51; Simanshu et al., Cell 2017, 170, 17-33.
[0004] A RAS protein is a small GTPase encoded by a RAS oncogene. Papke and Der, Science 2017, 355, 1158-63. The RAS protein functions as a molecular switch cycling between the active guanosine triphosphate (GTP)-bound and inactive guanosine diphosphate (GDP)- bound states. Milburn et al., Science 1990, 247, 939-45. The GTP-bound active RAS activates downstream effector pathways, including rat fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated kinase (RAF/MEK/ERK) and phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin kinase (PI3K/AKT/mTOR). Rebocho and Marais, Cancer 397Discov. 2011, 7, 98-9. Oncogenic mutations in RAS proteins impair their ability for GTP hydrolysis, resulting in the accumulation of GTP-bound active RAS and hyperactivation of downstream signaling cascades that lead to uncontrolled cell proliferation and survival. Uras et al., hit. J. Mol. Set. 2020, 21, 4325.
[0005] The RAS signaling is tightly regulated by guanine nucleotide exchange factor (GEF) proteins, which catalyze the exchange of GDP for GTP, and GTPase-activating proteins (GAPs), which increase the rate of GTP hydrolysis to GDP. Simanshu et al., Cell 2017, 170, 17- 33. In other words, the RAS GTP/GDP cycle is regulated negatively by GAPs and positively by GEFs. Bos, Cell 2007, 129, 865-77. The son of sevenless homolog 1 (S0S1) is a GEF that binds to RAS to promote nucleotide exchange and formation of GTP-bound active RAS. Wang et al., Bioorg. Med. Chem. Lett. 2012, 22, 5766-76. Small molecule S0S1 inhibitors have been shown to be effective in downregulating active RAS in tumor cells with wild-type KRAS as well as tumor cells bearing a KRAS mutation. Hillig et al., Proc. Nat. Acad. Set. 2019, 114, 2551-60. By preventing formation of the KRAS-SOS1 complex, the S0S1 inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. Id.
[0006] Despite the advances in cancer treatment, cancer remains a major worldwide public health problem. It was estimated that there will be 1,958,310 new cancer cases diagnosed and 609,820 cancer deaths in the US alone in 2023. Cancer Facts & Figures 2023. Therefore, there is a need for an effective therapy for cancer treatment.
SUMMARY OF THE DISCLOSURE
[0007] Provided herein is a compound of Formula (I):
Figure imgf000003_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
A is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
L is C1-6 alkylene, C7-15 aralkylene, or a linker;
U and V are each independently -C(R4a)= or -N=;
X is -N= or -C(R4b)=;
R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R3 is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c;
R2a and R2b are each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4a and R4b is independently hydrogen or R4;
Re is an E3 ubiquitin ligase binding moiety; each R1a, Rlb, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRe, -NRbRe, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRe, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRe, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Re, and Rd is independently (i) hydrogen or deuterium; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRs, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRs, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rb, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, R1, Rg, and Rb is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0008] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient. [0009] Additionally provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a son of sevenless homolog 1 (S0S1) in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0010] Furthermore, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a RAS in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0011] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0012] Provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[0013] Provided herein is a method of inducing degradation of an S0S1, comprising contacting the S0S1 with a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. DETAILED DESCRIPTION
[0014] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
[0015] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.
[0016] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.
[0017] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
[0018] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition.
[0019] The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.
[0020] The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.
[0021] The term “therapeutically effective amount” or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
[0022] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid fdler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; Adejare Ed.; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; Sheskey el al., Eds.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, Ist ed.; Gibson Ed.; CRC Press, 2015.
[0023] The term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, or 3 standard deviations. In certain embodiments, the term “about” or “approximately” means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
[0024] The term “alkyl” refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, Ci-6 alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkyl groups are also referred as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., //-propyl and isopropyl), butyl (including all isomeric forms, e.g., //-butyl, isobutyl, ec-butyl, and Ebutyl), pentyl (including all isomeric forms, e.g., //-pentyl, isopentyl, sec-pentyl, neopentyl, and Zc/7-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).
[0025] The terms “alkylene” and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6 alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30), 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Ci-e) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 alkanediyl groups are also referred as “lower alkanediyl.” Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane- 1 , 1 -diyl and ethane-1,2- diyl), propanediyl (including all isomeric forms, e.g., propane- 1,1 -diyl, propane- 1,2-diyl, and propane-l,3-diyl), butanediyl (including all isomeric forms, e.g, butane- 1,1 -diyl, butane-1,2- diyl, butane- 1,3 -diyl, and butane- 1,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane- 1,1 -diyl, pentane- 1,2-diyl, pentane- 1,3 -diyl, and pentane- 1,5 -diyl), and hexanediyl (including all isomeric forms, e.g., hexane- 1,1 -diyl, hexane- 1,2-diyl, hexane- 1,3 -diyl, and hexane- 1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, -C(O)CH2- -C(O)(CH2)2- -C(O)(CH2)3-, -C(O)(CH2)4- -C(O)(CH2)5- -C(O)(CH2)6- -C(O)(CH2)7-, -C(O)(CH2)8-, -C(O)(CH2)9-, -C(0)(CH2)IO-, -C(O)CH2C(O)-, -C(O)(CH2)2C(O)-, -C(O)(CH2)3C(O)-, -C(O)(CH2)4C(O)-, or -C(O)(CH2)5C(O)-.
[0026] The term “heteroalkyl” refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, Ci-6 heteroalkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (Ci-is), 1 to 10 (Ci-io), or 1 to 6 (Ci-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkyl groups are also referred as “lower heteroalkyl.” Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, -CH2NHC(O)CH3 and -NHC(O)CH2CH3.
[0027] The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6 heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (Ci -20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (Cue) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6 and branched C3-6 heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are not limited to, -CH2O-, -(CH2)2O-, -(Cfh^O-, -(CH2)4O- -(CH2)5O-, -(CH2)6O- -(CH2)7O-, -(CH2)SO-, -(CH2)9O-, -(CH2)IOO-, -CH2OCH2-, -CH2CH2O-, -(CH2CH2O)2-, -(CH2CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH- -CH2S-, -CH2SCH2-, and -CH2CH2S-. Examples of substituted heteroalkylene groups include, but are not limited to, -C(O)CH2O-, -C(O)(CH2)2O- -C(O)(CH2)3O- -C(O)(CH2)4O- -C(O)(CH2)5O- -C(O)(CH2)6O-, -C(O)(CH2)7O- -C(O)(CH2)SO-, -C(O)(CH2)9O-
C(0)(CH2)IOO , C(O)CH2OCH2CH2O , C(O)CH2O(CH2CH2O)2 , -C(O)CH2O(CH2CH2O)3-, -C(O)CH2O(CH2CH2O)4, -C(O)CH2O(CH2CH2O)5-, -CH2NHC(O)CH2-, or -CH2CH2C(O)NH-.
[0028] The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenyl is optionally substituted with one or more substituents Q as described herein. The term “alkenyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z”
Figure imgf000011_0001
configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen- 1-yl, propen-2 -yl, and allyl), and butenyl (including all isomeric forms, e.g., buten- 1-yl, buten-2-yl, buten-3-yl, and 2-buten-l-yl).
[0029] The terms “alkenylene” and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s). The alkenediyl is optionally substituted with one or more substituents Q as described herein. The term “alkenediyl” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z”
Figure imgf000012_0001
configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g., ethene- 1,1- diyl and ethene- 1,2-diyl), propenediyl (including all isomeric forms, e.g., 1 -propene- 1,1 -diyl, 1- propene-l,2-diyl, and 1 -propene- 1,3 -diyl), butenediyl (including all isomeric forms, e.g., 1- butene- 1,1 -diyl, 1 -butene- 1,2-diyl, and 1 -butene- 1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1 -pentene- 1,1 -diyl, l-pentene-l,2-diyl, and 1 -pentene- 1,5 -diyl), and hexenediyl (including all isomeric forms, e.g., 1 -hexene- 1,1 -diyl, 1 -hexene- 1,2-diyl, l-hexene-l,3-diyl, 1- hexene- 1,4-diyl, 1 -hexene- 1,5 -diyl, and 1 -hexene- 1,6-diyl).
[0030] The terms “heteroalkenylene” and “heteroalkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain. The heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term “heteroalkenylene” embraces radicals having a "cis" or "trans ' configuration or a mixture thereof, or alternatively, a “Z” or “£” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6 heteroal kenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2- -CH=CHCH2O- -CH=CHS- -CH=CHSCH2- -CH=CHCH2S- or -CH=CHCH2NH- [0031 ] The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynyl group does not contain a carboncarbon double bond. The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C=CH), propynyl (including all isomeric forms, e.g., 1-propynyl (-OCCH3) and propargyl (-CH2OCH)), butynyl (including all isomeric forms, e.g., 1-butyn-l-yl and 2-butyn- 1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-l-yl and l-methyl-2-butyn-l-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-l-yl and 2-hexyn-l-yl).
[0032] The terms “alkynylene” and “alkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). An alkynylene group does not contain a carbon-carbon double bond. The alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6 alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4- e) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1 -propyne- 1,3 -diyl and l-propyne-3,3-diyl), butynediyl (including all isomeric forms, e.g., l-butyne-l,3-diyl, 1 -butyne- 1,4-diyl, and 2- butyne- 1,1 -diyl), pentynediyl (including all isomeric forms, e.g., l-pentyne-l,3-diyl, 1-pentyne- 1,4-diyl, and 2-pentyne- 1,1 -diyl), and hexynediyl (including all isomeric forms, e.g., 1-hexyne- 1,3-diyl, 1 -hexyne- 1,4-diyl, and 2-hexyne- 1,1 -diyl). [0033] The terms “heteroal kynylene” and “heteroalkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s), and which contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. A heteroalkynylene group does not contain a carbon-carbon double bond. The heteroalkynylene is optionally substituted with one or more substituents Q as described herein. For example, C2-6 heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, the heteroalkynylene is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2- 6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of heteroalkynylene groups include, but are not limited to, -C^CCIEO-, -C^CCFFS-. or OCCH2NH .
[0034] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and/or bridged or non-bridged, and/or fused bicyclic group. In certain embodiments, the cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[l. l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.
[0035] The terms “cycloalkylene” and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and/or bridged, and/or non-bridged, and/or fused bicyclic groups. In certain embodiments, the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane- 1,1 -diyl and cyclopropane- 1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane- 1, 1 -diyl, cyclobutane- 1,2-diyl, and cyclobutane- 1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane- 1,1 -diyl, cyclopentane- 1,2-diyl, and cyclopentane- 1,3 -diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane-l,l-diyl, cyclohexane- 1,2-diyl, cyclohexane-l,3-diyl, and cyclohex-1, 4- diyl), cycloheptanediyl (including all isomeric forms, e.g., cycloheptane- 1,1 -diyl, cycloheptane- 1,2-diyl, cycloheptane- 1,3 -diyl, and cycloheptane-l,4-diyl), decalinediyl (including all isomeric forms, e.g., decaline- 1,1 -diyl, decaline-1, 2-diyl, and decaline-1, 8-diyl), and adamantdiyl (including all isomeric forms, e.g., adamant- 1,2-diyl, adamant- 1,3 -diyl, and adamant- 1,8-diyl).
[0036] The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and/or monovalent polycyclic aromatic hydrocarbon radical that contain at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-is), or from 6 to 10 (C6-io) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.
[0037] The terms “arylene” and “arenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has from 6 to 20 (C6-20), from 6 to 15 (C6-is), or from 6 to 10 (C6-io) ring atoms. Examples of arylene groups include, but are not limited to, phenylene (including all isomeric forms, e.g., phen- 1,2-diyl, phen-l,3-diyl, and phen-l,4-diyl), naphthylene (including all isomeric forms, e.g., naphth- 1,2-diyl, naphth- 1,3 -diyl, and naphth- 1,8-diyl), fluorenylene (including all isomeric forms, e.g., fluoren-l,2-diyl, fluoren- 1,3 -diyl, and fluoren- 1,8-diyl), azulenylene (including all isomeric forms, e.g., azulen- 1,2-diyl, azulen- 1,3 -diyl, and azulen-1,8- diyl), anthrylene (including all isomeric forms, e.g., anthr-l,2-diyl, anthr- 1,3 -diyl, and anthr-1,8- diyl), phenanthrylene (including all isomeric forms, e.g., phenanthr-l,2-diyl, phenanthr-l,3-diyl, and phenanthr-l,8-diyl), pyrenylene (including all isomeric forms, e.g., pyren-l,2-diyl, pyren- 1,3-diyl, and pyren-l,8-diyl), biphenylene (including all isomeric forms, e.g., biphen-2,3-diyl, biphen-3,4’-diyl, and biphen-4,4’-diyl), and terphenylene (including all isomeric forms, e.g., terphen-2,3-diyl, terphen-3,4’-diyl, and terphen-4,4’-diyl). Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth- 1,2-diyl and dihydronaphth- 1 ,8-diyl), indenylene (including all isomeric forms, e.g., inden- 1,2-diyl, inden- 1,5-diyl, and inden-l,7-diyl), indanylene (including all isomeric forms, e.g., indan- 1,2-diyl, indan- 1,5 -diyl, and indan- 1 ,7-diyl), or tetrahydronaphthylene (tetralinyl ene) (including all isomeric forms, e.g., tetrahydronaphth- 1 ,2- diyl, tetrahydronaphth-l,5-diyl, and tetrahydronaphth- 1 ,8-diyl). In certain embodiments, arylene is optionally substituted with one or more substituents Q as described herein.
[0038] The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2- phenylethyl), and phenylpropyl (including all isomeric forms, e.g, 1 -phenylpropyl, 2- phenylpropyl, and 3 -phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.
[0039] The term “aralkylene” or “arylalkylene” refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethdiyl), phenylethylene (including all isomeric forms, e.g., 2-phenyl-ethan- 1,1 -diyl and 2-phenyl-ethan-l,2-diyl), and phenyl propylene (including all isomeric forms, e.g., 3-phenyl- propan- 1,1 -diyl, 3-phenyl-propan-l,2-diyl, and 3-phenyl-propan-l,3-diyl). In certain embodiments, the aralkylene is optionally substituted with one or more substituents Q as described herein. [0040] The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring. For a heteroaryl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroaryl group is not bonded to the rest of a molecule through its nonaromatic heterocyclic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-Z>]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-/>]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-/>]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-rz]pyridinyl, imidazo[4,5- Z>]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2,l-Z>]thiazolyl and imidazo[4,5- ]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, e.g., 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5- Z>]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-Z>]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3- />]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-Z>]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4-d]pyrimidinyl and [l,2,3]thiadiazolo[4,5- ]pyrimidinyl), and thienopyridyl (including all isomeric forms, e.g., thieno[2,3-6]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-Z>]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7- phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.
[0041] The terms “heteroarylene” and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N. For a heteroarylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heteroarylene group is not bonded to the rest of a molecule via its nonaromatic heterocyclic ring. Each ring of a heteroarylene group can contain one or two O atoms, one or two S atoms, and/or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrrol diyl, thiadiazoldiyl, thiazoldiyl, thiendiyl, tetrazol diyl, triazinediyl, and triazol diyl. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofurandiyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadiazoldiyl, benzothiazoldiyl, benzothiendiyl, benzotriazoldiyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g., furo[2,3-Z?]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2-/>]pyridindiyl, furo[3,2-c]- pyridindiyl, furo[3,4-Z>]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g., imidazo[l,2-rz]pyridindiyl, imidazo[4,5-/>]pyridindiyl, and imidazo[4,5-c]- pyridindiyl), imidazothiazoldiyl (including all isomeric forms, e.g., imidazo[2,l-£>]thiazoldiyl and imidazo[4,5- ]thiazoldiyl), indazoldiyl, indolizindiyl, indoldiyl, isobenzofurandiyl, isobenzothiendiyl (i.e., benzo[c]thiendiyl), isoindoldiyl, isoquinolindiyl, naphthyridindiyl (including all isomeric forms, e.g., 1,5-naphthyridindiyl, 1,6-naphthyridindiyl, 1,7- naphthyridindiyl, and 1,8-naphthyridindiyl), oxazolopyridindiyl (including all isomeric forms, e.g., oxazolo[4,5-Z>]pyridindiyl, oxazolo[4,5-c]pyridindiyl, oxazolo[5,4-Z>]pyridindiyl, and oxazolo[5,4-c]pyridindiyl), phthalazindiyl, pteridindiyl, purindiyl, pyrrolopyridindiyl (including all isomeric forms, e.g., pyrrolo[2,3-Z>]pyridindiyl, pyrrolo[2,3-c]pyridindiyl, pyrrolo[3,2-/>]- pyridindiyl, and pyrrolo[3,2-c]pyridindiyl), quinolindiyl, quinoxalindiyl, quinazolindiyl, thiadiazolopyrimidindiyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4- ]- pyrimidindiyl and [l,2,3]thiadiazolo[4,5-d]pyrimidindiyl), and thienopyridindiyl (including all isomeric forms, e.g., thieno[2,3-Z>]pyridindiyl, thieno[2,3-c]pyridindiyl, thieno[3,2-Z>]pyridindiyl, and thieno[3,2-c]pyridindiyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridindiyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5-phenanthrolindiyl, 1,6- phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10-phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q as described herein.
[0042] The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non-aromatic ring system or monovalent polycyclic ring system that contains at least one nonaromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclyl group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclyl group is not bonded to the rest of a molecule through the heteroaromatic ring. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of heterocyclyls and heterocyclic groups include, but are not limited to, azepinyl, benzodioxanyl, benzodi oxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., l,4-dihydrobenzo[<7][l,3]oxazinyl, 3,4-dihydrobenzo[c][l,2]-oxazinyl, and 3,4-dihydrobenzo[ ][l,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.
[0043] The term “heterocyclylene” refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a heterocyclylene group containing a heteroaromatic ring and a nonaromatic heterocyclic ring, the heterocyclylene group has at least one bond to the rest of a molecule via its nonaromatic heterocyclic ring. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quatemized, and some rings may be partially or fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclylene groups include, but are not limited to, azepindiyl, benzodi oxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e. ., l,4-dihydrobenzo[6 ][l,3]oxazindiyl, 3,4-dihydrobenzo[c][l,2]oxazindiyl, and 3,4-dihydrobenzo[ ][l,2]oxazindiyl), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydroisoindoldiyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrrol diyl, dioxolandiyl, 1,4-dithiandiyl, furanondiyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandiyl, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholindiyl, octahydroindoldiyl, octahydroisoindoldiyl, oxazolidinondiyl, oxazolidindiyl, oxirandiyl, piperazindiyl, piperidindiyl, 4-piperidondiyl, pyrazolidindiyl, pyrazolindiyl, pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydroisoquinolindiyl, tetrahydropyrandiyl, tetrahydrothiendiyl, thiamorpholindiyl, thiazolidindiyl, thiochromandiyl, tetrahydroquinolindiyl, and 1,3,5-trithiandiyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q as described herein.
[0044] The term “halogen,” “halide,” or “halo” refers to fluoro, chloro, bromo, and/or iodo.
[0045] The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO2), and oxo (=0); (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -0C(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally substituted.”
[0046] In one embodiment, each Qa is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORC, -OC(O)NRfRg, -OC(O)SRC, -OC(NRc)NRfRs, -OC(S)RC, -OC(S)ORC, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-i4 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
[0047] In certain embodiments, “optically active” and ’’enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question. In certain embodiments, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer based on the total weight of the enantiomeric mixture in question.
[0048] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the compound, R and S. [0049] The term “isotopically enriched” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon- 11 (UC), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (13O), oxygen-16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (3?C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon- 12 (12C), carbon- 13 (13C), nitrogen- 14 (14N), nitrogen- 15 (15N), oxygen- 16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur- 33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), and iodine-127 (127I). In certain embodiments, an isotopically enriched compound is in an unstable form, that is, radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (UC), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36C1), iodine-123 (123I), iodine-125 (125I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be 2H, as example, or any carbon can be 13C, as example, or any nitrogen can be 15N, as example, or any oxygen can be 18O, as example, where feasible according to the judgment of one of ordinary skill in the art.
[0050] The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope e.g., 1H for protium or hydrogen-1) of the element. As used herein, when an atom at a particular position in a molecule is designated as a particular less prevalent isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.
[0051] The term “isotopic enrichment factor” refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.
[0052] The term “hydrogen” or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium (1H), deuterium (2H or D), and tritium (3H), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.
[0053] The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).
[0054] The term “carbon” or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon- 12 (12C) and carbon- 13 (13C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.
[0055] The term “carbon-13 enrichment” or “13C enrichment” refers to the percentage of incorporation of carbon- 13 at a given position in a molecule in the place of carbon. For example, carbon- 13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon- 13 at the specified position. Because the naturally occurring distribution of carbon- 13 is about 1.11% on average, carbon- 13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).
[0056] The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, including a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular less prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.
[0057] The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, //-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate. [0058] For a divalent group described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.
[0059] The phrase “an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof’ has the same meaning as the phrase “(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referenced therein.”
Compounds
[0060] In one embodiment, provided herein is a compound of Formula (I):
Figure imgf000026_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
A is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
L is C1-6 alkylene, C7-15 aralkylene, or a linker;
U and V are each independently -C(R4a)= or -N=;
X is -N= or -C(R4b)=;
R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R3 is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4 is independently (i) deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c;
R2a and R2b are each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4a and R4b is independently hydrogen or R4;
Re is an E3 ubiquitin ligase binding moiety; each R1a, Rlb, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORe, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc,
NRaC(O)SRd, NRaC(NRd)NRbRc, NRaC(S)Rd, NRaC(S)ORd, NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRe, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRs, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, OC(O)NRfRg, OC(O)SRe, OC(NRe)NRfRg, OC(S)Re, OC(S)ORe, OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R1 and R8 together with the N atom to which they are attached form heterocyclyl.
[0061] In certain embodiments, in any one of the formulae described herein, A is C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is monocyclic C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is bicyclic C4-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is bridged, fused, or spiro C4-10 cycloalkylene, each optionally substituted with one or more substituents Q.
[0062] In certain embodiments, in any one of the formulae described herein, A is C6-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phendiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phendiyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently halo, Ci-6 alkyl, or Ci-6 heteroalkyl. In certain embodiments, in any one of the formulae described herein, A is phendiyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, A is phen-l,2-diyl, phen-l,3-diyl, or phen-l,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phen- 1,3 -diyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phen-l,3-diyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently halo, Ci-6 alkyl, or Ci-6 heteroalkyl. In certain embodiments, in any one of the formulae described herein, A is phen- 1,3 -diyl, optionally substituted with one, two, or three substituents Q, wherein each substituent is independently fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, A is phen-l,3-diyl, 2-fluorophen- 1,3 -diyl, 4-fluorophen- 1,3 -diyl, 5 -fluorophen- 1,3 -diyl, 2- chlorophen-l,3-diyl, 4-chlorophen-l,3-diyl, 5-chlorophen-l,3-diyl, 2-methylphen- 1,3 -diyl, 4- methylphen- 1,3 -diyl, or 5-methylphen-l,3-diyl.
[0063] In certain embodiments, in any one of the formulae described herein, A is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 5-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 6-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is furandiyl, thiendiyl, or pyridindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is furan-2,4-diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, or pyridin-3,5-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q.
[0064] In certain embodiments, in any one of the formulae described herein, A is heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is 1,2-dihydro- pyridindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is l,2-dihydropyridin-l,5-diyl, l,2-dihydropyridin-3,5-diyl, piperidin-l,3-diyl, morpholin-2,4- diyl, or piperazin- 1 ,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is l-methyl-2-oxo-l,2- dihydropyri din-3, 5-diyl, 2-oxo-l,2-dihydropyridin-l,5-diyl, 3-fluoropiperidin-l,3-diyl, morpholin-2,4-diyl, or piperazin- 1 ,4-diyl. In certain embodiments, in any one of the formulae described herein, A is bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q.
[0065] In certain embodiments, in any one of the formulae described herein, A is C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phendiyl, monocyclic heteroarylene, or monocyclic heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phendiyl, furandiyl, thiendiyl, pyridindiyl, 1,2-dihydropyridindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, A is phen-l,3-diyl, furan-2,4- diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-3, 5-diyl, l,2-dihydropyridin-3,5- diyl, 1,2-dihydropyridin-l, 5-diyl, morpholin-2,4-diyl, piperazin- 1,4-diyl, or piperi din- 1,3 -diyl, each optionally substituted with one or more substituents Q.
[0066] In certain embodiments, in any one of the formulae described herein, A has the structure
Figure imgf000031_0001
wherein:
U5, V5, X5, and Z5 are each independently -C(R5)= or -N=;
U6 is -C(R6b)2- or -O-; each R5, R6a, and R6b is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1 bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; each R6 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, C(O)OR1a, C(O)NR1 bR1c, C(O)SR1a, C(NR1 a)NR1bR1c, C(S)R1a, C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1 bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1 bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1 bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NRlbR1c, or -S(O)2NR1bR1c; b is an integer of 0, 1, 2, 3, 4, 5, or 6; and R1a, Rlb, R1c, and R1d are each as defined herein.
[0067] In one embodiment, provided herein is a compound of Formula (II):
Figure imgf000032_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R3, R4, R2a, R2b, Re, L, U, V, X, U3, V5, X5, Z5, and a are each as defined herein.
[0068] In another embodiment, provided herein is a compound of Formula (III):
Figure imgf000032_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R3, R4, R6, R2a, R2b, R6a, Re, L, U, V, X, U6, a, and b are each as defined herein.
[0069] In certain embodiments, in any one of the formulae described herein, R3 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is monocyclic C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is bicyclic C4-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is bridged, fused, or spiro C4-10 cycloalkyl, each optionally substituted with one or more substituents Q.
[0070] In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, substituted with three substituents Q.
[0071] In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methyl- propyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylamino- methylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, nitro, methyl, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, methyl, difluoromethyl, trifluoromethyl, or amino.
[0072] In certain embodiments, in any one of the formulae described herein, R3 is phenyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is phenyl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is phenyl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R3 is phenyl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is phenyl, substituted with three substituents Q.
[0073] In certain embodiments, in any one of the formulae described herein, R3 is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3 is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2- hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl-phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3 is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, nitro, methyl, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3 is phenyl, substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, methyl, difluoromethyl, trifluoromethyl, or amino.
[0074] In certain embodiments, in any one of the formulae described herein, R3 is 3- cyanophenyl, 3-bromophenyl, 3 -methylphenyl, 3 -difluorom ethylphenyl, 3 -trifluorom ethylphenyl, 3-(l-cyano-l,l-difhioromethyl)phenyl, 3-(l,l-difhioro-2-hydroxyethyl)phenyl, 3-(2- aminomethylphenyl)phenyl, 3-cyano-5-fluorophenyl, 3-cyano-2-methylphenyl, 3-cyano-5- methylphenyl, 3-cyano-2-trifluoromethylphenyl, 3-cyano-5-hydroxyphenyl, 3 -cyano-2-m ethoxyphenyl, 3-nitro-5-trifluoromethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2-chloro-3- fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-3 -difluorom ethylphenyl, 2-chl oro-3 -methylphenyl, 3-chloro-2-methylphenyl, 3-difluoromethyl-2-fluorophenyl, 3-difluoromethyl-2-fluoro- methylphenyl, 3 -difluorom ethyl-2-ethylphenyl, 3 -difluorom ethyl-2-methylphenyl, 2-fluoro-3- (1,1 -difl uoro-2-hydroxy-2-methylpropyl)phenyl, 2-fluoro-3 -methylphenyl, 3-fluoro-2-methyl- phenyl, 3 -fluoro-4-m ethylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-3 -trifluoromethylphenyl, 3- fluoro-5-trifluoromethylphenyl, 2,3-di(difluoromethyl)phenyl, 2-methyl-3 -trifluorom ethylphenyl, 2-methyl-3-methylaminomethylphenyl, 2-methyl-3-methylsulfonylphenyl, 3-methyl-5- trifluoromethylphenyl, 3-hydroxy-5-trifluoromethylphenyl, 3-amino-5-trifluoromethylphenyl, 3- amino-4-fluoro-5-trifluoromethylphenyl, 5-amino-2-fluoro-3 -trifluoromethylphenyl, 5-amino-2- methyl-3 -trifluoromethylphenyl, 3-cyano-2,5-difluorophenyl, 3-cyano-5-fluoro-2-methylphenyl, or 5-fluoro-2-methyl-3-trifluoromethylphenyl. In certain embodiments, in any one of the formulae described herein, R3 is 3-difluoromethyl-2-fluorophenyl, 3-difluoromethyl-2-methyl- phenyl, 3-cyano-2-methylphenyl, 3-nitro-5-trifluoromethylphenyl, 3-fluoro-2-methylphenyl, 2- methyl-3 -trifluoromethylphenyl, or 3-amino-5-trifluoromethylphenyl. In certain embodiments, in any one of the formulae described herein, R3 is 3-difluoromethyl-2-fluorophenyl, 3-difluoro- methyl-2-methylphenyl, 3-cyano-2-methylphenyl, 3-fluoro-2-methylphenyl, 2-methyl-3- trifluoromethylphenyl, or 3 -amino-5-trifluorom ethylphenyl.
[0075] In certain embodiments, in any one of the formulae described herein, R3 is bicyclic Cs-14 aryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is bicyclic Cs-i4 aryl, substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is bicyclic Cs-14 aryl, substituted with one substituent Q. In certain embodiments, in any one of the formulae described herein, R3 is bicyclic Cs-14 aryl, substituted with two substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is bicyclic Cs-14 aryl, substituted with three substituents Q.
[0076] In certain embodiments, in any one of the formulae described herein, R3 is 5,6- or 6,6-fused C9-14 aryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 2,3-dihydroindenyl or naphthyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 2,3-dihydroindenyl or naphthyl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano, halo, or nitro; (ii) C1-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1 bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3 is 2,3-dihydroinden-4-yl, 2,3-dihydroinden-5-yl, naphth-l-yl, or naphth-2-yl, each optionally substituted with one, two, or three substituents, each of which is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2- hydroxy ethyl, l,l-difluoro-2-hydroxy-2-m ethylpropyl, methylaminomethyl, 2-aminom ethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3 is l,l-difluoro-2,3-dihydroinden-4-yl or naphth-l-yl. [0077] In certain embodiments, in any one of the formulae described herein, R3 is heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is monocyclic heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 5- or 6-membered heteroaryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is thienyl or pyridinyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is thien-2-yl or thien-3-yl, each independently substituted with C6-14 aryl or heteroaryl, where the aryl and heteroaryl are each optionally further substituted with one, two, or three substituents Qa. In certain embodiments, in any one of the formulae described herein, R3 is thienyl or pyridinyl, each optionally substituted with one, two, or three substituents, each of which is independently (i) cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3 is thien- 2-yl, thien-3-yl, pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, each optionally substituted with one, two, or three substituents, wherein each substituent is independently cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoro- methyl, 1,1 -difl uoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethylphenyl, 2- dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3 is thien-2-yl, 5-(2-hydroxy- methylphenyl)thien-2-yl, 5-(2-aminomethylphenyl)thien-2-yl, 4-(2-methylaminomethylphenyl)- thien-2-yl, or 5-(2-(2-aminoethyl)phenyl)thien-2-yl. In certain embodiments, in any one of the formulae described herein, R3 is bicyclic heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 5,5-fused heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 5,6-fused heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 6,6-fused heteroaryl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is thien- 2-yl, 5-(2-hydroxymethyl-phenyl)thien-2-yl, 5-(2-amino-methylphenyl)thien-2-yl, 4-(2-methyl- aminomethylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)-phenyl)thien-2-yl, or 5-(6,7-dihydro- py rrol o [ 1 ,2-a] imi dazol -3 -y 1 )thi en-2-y 1.
[0078] In certain embodiments, in any one of the formulae described herein, R3 is heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is monocyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is bicyclic heterocyclyl, optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is bridged, fused, or spiro heterocyclyl, each optionally substituted with one, two, or three substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is 2,3- dihydrobenzofuranyl, optionally substituted with one, two, or three substituents Q.
[0079] In certain embodiments, in any one of the formulae described herein, R3 is C6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3 is phenyl or monocyclic heteroaryl, each optionally substituted with one or more substituents Q.
[0080] In certain embodiments, in any one of the formulae described herein, R3 is 3- cyanophenyl, 3 -bromophenyl, 3 -methylphenyl, 3 -difluoromethylphenyl, 3 -trifluorom ethylphenyl, 3-(l,l-difhioroethyl)phenyl, 3-(l-cyano-l-fluoromethyl)phenyl, 3-(l-cyano-l,l-difluoro- methyl)phenyl, 3-(l,l-difluoro-2-hydroxyethyl)phenyl, 3-(2-aminomethylphenyl)phenyl, 3- cyano-5-fluorophenyl, 3-cyano-2-methylphenyl, 3-cyano-5-methylphenyl, 3-cyano-2-trifluoro- methylphenyl, 3-cyano-5-hydroxyphenyl, 3-cyano-2-methoxyphenyl, 3 -nitro-5-trifluorom ethylphenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluoro- phenyl, 2-chloro-3-difluoromethylphenyl, 2-chl oro-3 -methylphenyl, 3 -chloro-2-m ethylphenyl, 3- difhroromethyl-2-fluorophenyl, 3-difluoromethyl-2-methylphenyl, 2-fluoro-3-(l, l-difluoro-2- hydroxy-2-methylpropyl)phenyl, 2-fluoro-3 -methylphenyl, 3-fluoro-2-methylphenyl, 3-fluoro-4- methylphenyl, 4-fluoro-2-methylphenyl, 2-fluoro-3 -difluoromethylphenyl, 2-fluoro-3 -trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl, 2-fluoromethyl-3-difluoromethylphenyl, 2,3- di(difluoromethyl)phenyl, 2-methyl-3-trifluoromethylphenyl, 2-ethyl-3 -difluoromethylphenyl, 2- methyl-3 -methylaminomethylphenyl, 2-methyl-3 -methylsulfonylphenyl, 3-methyl-5-trifluoro- methylphenyl, 3-hydroxy-5-trifluoromethylphenyl, 3-amino-5-trifluoromethylphenyl, 3-amino-4- fluoro-5-trifluoromethylphenyl, 5 -amino-2-fluoro-3 -trifluoromethylphenyl, 5-amino-2-methyl-3- trifluoromethylphenyl, 3-cyano-2,5-difluorophenyl, 3-cyano-5-fluoro-2-methylphenyl, 5-fluoro- 2-methyl-3-trifluoromethylphenyl, l,l-difluoro-2,3-dihydroinden-4-yl, naphth-l-yl, 5-(2-amino- methylphenyl)thien-2-yl, 5-(2-(2-aminoethyl)phenyl)thien-2-yl, 4-(2-methylaminomethyl- phenyl)thien-2-yl, 4-(2-dimethylaminomethylphenyl)thien-2-yl, 5-(2-methylaminomethyl- phenyl)thien-2-yl, 5-(3-fluoro-2-methylaminomethylphenyl)thien-2-yl, 5-(2-dimethylamino- methylphenyl)thien-2-yl, 2-methyl-pyri din-3 -yl, 4-amino-6-difluoromethylpyridin-2-yl, 4- amino-6-trifluoromethylpyridin-2-yl, or 3,3-difluoro-2,3-dihydrobenzofuran-7-yl.
[0081] In certain embodiments, in any one of the formulae described herein, R2b is hydrogen. In certain embodiments, in any one of the formulae described herein, R2b is deuterium. In certain embodiments, in any one of the formulae described herein, R2b is halo. In certain embodiments, in any one of the formulae described herein, R2b is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2b is heterocyclyl, optionally substituted with one or more substituents Q.
[0082] In one embodiment, provided herein is a compound of Formula (IV):
Figure imgf000039_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
R3a, R3b, R3C, R3d, and R3e are each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1 a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1 aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; and
R1, R4, R1a, Rlb, R1c, R1d, R2a, Re, L, U, V, X, U5, V5, X5, Z5, and a are each as defined herein.
[0083] In another embodiment, provided herein is a compound of Formula (V):
Figure imgf000040_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R6a, Re, L, U, V, X, U6, a, and b are each as defined herein.
[0084] In certain embodiments, in any one of the formulae described herein, X is -C(R4b)=, wherein R4b is as defined herein. In certain embodiments, in any one of the formulae described herein, X is -C(H)=. In certain embodiments, in any one of the formulae described herein, X is -N=.
[0085] In certain embodiments, in any one of the formulae described herein, U is -C(R4a)=; V is -N=; and X is -C(R4b)=; wherein R4a and R4b are each as defined herein. In certain embodiments, in any one of the formulae described herein, U is -N=; V is -C(R4a)=; and X is -C(R4b)=; wherein R4a and R4b are each as defined herein.
[0086] In one embodiment, provided herein is a compound of Formula (VI):
Figure imgf000040_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, Re, L, U, V, U5, V5, X5, Z5, and a are each as defined herein.
[0087] In another embodiment, provided herein is a compound of Formula (VII):
Figure imgf000041_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R6a, Re, L, U, V, U6, a, and b are each as defined herein.
[0088] In certain embodiments, in any one of the formulae described herein, U is -C(R4a)=, wherein R4a is as defined herein. In certain embodiments, in any one of the formulae described herein, U is -C(R4a)=, wherein R4a is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, U is -C(CH3)=. In certain embodiments, in any one of the formulae described herein, U is -N=.
[0089] In certain embodiments, in any one of the formulae described herein, V is -C(R4a)=, wherein R4a is as defined herein. In certain embodiments, in any one of the formulae described herein, V is -C(R4a)=, wherein R4a is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, V is -C(CH3)=. In certain embodiments, in any one of the formulae described herein, V is -N=.
[0090] In one embodiment, provided herein is a compound of Formula (VIIIA):
Figure imgf000042_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re, L, U5, V5, X5, Z5, and a are each as defined herein.
[0091] In another embodiment, provided herein is a compound of Formula (VIIIB):
Figure imgf000042_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re, L, U5, V5, X5, Z5, and a are each as defined herein.
[0092] In one embodiment, provided herein is a compound of Formula (IXA):
Figure imgf000042_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.
[0093] In another embodiment, provided herein is a compound of Formula (XA):
Figure imgf000043_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.
[0094] In yet another embodiment, provided herein is a compound of Formula (XIA):
Figure imgf000043_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.
[0095] In one embodiment, provided herein is a compound of Formula (IXB):
Figure imgf000044_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.
[0096] In yet another embodiment, provided herein is a compound of Formula (XB):
Figure imgf000044_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3c, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.
[0097] In yet another embodiment, provided herein is a compound of Formula (XIB):
Figure imgf000045_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R6, R2a, R3a, R3b, R3C, R3d, R3e, R4a, R6a, Re, L, U6, a, and b are each as defined herein.
[0098] In certain embodiments, in any one of the formulae described herein, Re is a moiety of a cereblon (CRBN) E3 ligand.
[0099] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (El):
Figure imgf000045_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein:
Ae is a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene; Z is -CH2- or -C(O)-; one of Z1, Z2, Z3, and Z4 is C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(Re4)=; or Z1 is a bond; one of Z2, Z3, and Z4 is -C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(Re4)= or -S-;
Re1 is hydrogen, deuterium, halo, or C1-6 alkyl;
Re2 is hydrogen or C1-6 alkyl; each Re3 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1 aC(O)OR1d, -NR1aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; each Re4 is independently hydrogen or Re3; m is an integer of 0, 1, or 2; and R1a, Rlb, R1c, and R1d are each as defined herein; wherein each alkyl, heteroalkyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.
[00100] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (Eli):
Figure imgf000046_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0, 1, 2, or 3; and Ae, Re1, Re2, Re3, Z, and m are each as defined herein.
[00101] In certain embodiments, in any one of the formulae described herein, Rc is a moiety having the structure of Formula (EIII):
Figure imgf000046_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.
[00102] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EIV):
Figure imgf000047_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.
[00103] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EV):
Figure imgf000047_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.
[00104] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EVI):
Figure imgf000047_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and Ae, Re1, Re2, Re3, Z, and m are each as defined herein.
[00105] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EVII):
Figure imgf000048_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.
[00106] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EVIII):
Figure imgf000048_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.
[00107] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EIX):
Figure imgf000048_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and Ae, Re1, Re2, Re3, Z, and m are each as defined herein.
[00108] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EX):
Figure imgf000048_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.
[00109] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXI):
Figure imgf000049_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.
[00110] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXII):
Figure imgf000049_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein n is an integer of 0 or 1; and Ae, Re1, Re2, Re3, Z, and m are each as defined herein.
[00111] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXIII):
Figure imgf000049_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein. [00112] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXIV):
Figure imgf000050_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re4, Z, and m are each as defined herein.
[00113] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXV):
Figure imgf000050_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein:
Xc is C(Rcl) or N;
Re5 is (i) hydrogen; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1 a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; and
Ae, R1a, Rlb, R1c, R1d, Re1, Re2, Re3, m, and n are each as defined herein.
[00114] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXVI):
Figure imgf000051_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re3, Re5, m, and n are each as defined herein.
[00115] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXVII):
Figure imgf000051_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re3, Re5, m, and n are each as defined herein.
[00116] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXVIII):
(EXVIII)
Figure imgf000051_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re3, Re5, m, and n are each as defined herein.
[00117] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXIX):
Figure imgf000052_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re2, Re3, Re5, m, and n are each as defined herein.
[00118] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXX):
Figure imgf000052_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re2, Re3, Rw, m, and n are each as defined herein.
[00119] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXI):
Figure imgf000052_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re2, Re3, Re?, m, and n are each as defined herein.
[00120] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXII): (EXXII)
Figure imgf000053_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re2, Re3, Xe, m, and n are each as defined herein.
[00121] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXIII):
(EXXIII)
Figure imgf000053_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re3, m, and n are each as defined herein.
[00122] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXIV):
(EXXIV)
Figure imgf000053_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re2, Re3, m, and n are each as defined herein.
[00123] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXV):
Figure imgf000053_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ac, Rcl, Rc2, Rc3, m, and n are each as defined herein.
[00124] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXVI):
(EXXVI)
Figure imgf000054_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re2, Re3, m, and n are each as defined herein.
[00125] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXVII):
(EXXVII)
Figure imgf000054_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re2, Re3, m, and n are each as defined herein.
[00126] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXII):
(EXXVIII)
Figure imgf000054_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re2, Re3, m, and n are each as defined herein. [00127] In one embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (El), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (Eli), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Rc is a moiety having the structure of Formula (EXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00128] In one embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXIX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXX), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00129] In one embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXIV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXV), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXVI), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXVII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula (EXXVIII), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00130] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of:
Figure imgf000058_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae and Re4 are each as defined herein.
[00131] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula El, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of Formula E2, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00132] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of:
Figure imgf000058_0002
Figure imgf000059_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00133] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of:
Figure imgf000059_0002
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. [00134] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of:
Figure imgf000060_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, and Re4 are each as defined herein.
[00135] In one embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E3, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E4, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E5, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E6, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E7, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E8, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00136] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of:
Figure imgf000061_0001
Figure imgf000062_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00137] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of:
Figure imgf000062_0002
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein Ae, Re1, Re3, and n are each as defined herein.
[00138] In one embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E9, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E10, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula Ell, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula Ell, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In yet another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E13, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof. In still another embodiment, in any one of the formulae described herein, Re is a moiety having the structure of Formula E14, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00139] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of:
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00140] In certain embodiments, in any one of the formulae described herein, Re is a moiety having the structure of:
Figure imgf000065_0002
Figure imgf000066_0001
or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
[00141] In one embodiment, provided herein is a compound of Formula (XIIA):
Figure imgf000066_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re4, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00142] In another embodiment, provided herein is a compound of Formula (XIIIA):
Figure imgf000067_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00143] In one embodiment, provided herein is a compound of Formula (XIIB):
Figure imgf000067_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00144] In another embodiment, provided herein is a compound of Formula (XIIIB):
Figure imgf000068_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00145] In one embodiment, provided herein is a compound of Formula (XIVA):
Figure imgf000068_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, Xe, and a are each as defined herein.
[00146] In another embodiment, provided herein is a compound of Formula (XV A):
Figure imgf000069_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X3, Z3, and a are each as defined herein.
[00147] In yet another embodiment, provided herein is a compound of Formula (XVIA):
Figure imgf000069_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X3, Z3, and a are each as defined herein.
[00148] In yet another embodiment, provided herein is a compound of Formula (XVIIA):
Figure imgf000069_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00149] In still another embodiment, provided herein is a compound of Formula
(XVIII A):
Figure imgf000070_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3c, R4a, Rc2, Rc4, Rc5, Ac, L, U5, V5, X5, Z5, and a are each as defined herein.
[00150] In one embodiment, provided herein is a compound of Formula (XIVB):
Figure imgf000070_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3c, R4a, Rc2, Rc4, Rc5, Ac, L, U5, V5, X5, Z5, Xc, and a are each as defined herein.
[00151] In another embodiment, provided herein is a compound of Formula (XVB):
Figure imgf000071_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00152] In yet another embodiment, provided herein is a compound of Formula (XVIB):
Figure imgf000071_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, IF, V2, X5, Z5, and a are each as defined herein.
[00153] In yet another embodiment, provided herein is a compound of Formula (XVIIB):
Figure imgf000072_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00154] In still another embodiment, provided herein is a compound of Formula (XVIIIB):
Figure imgf000072_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3c, R3d, R3e, R4a, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00155] In one embodiment, provided herein is a compound of Formula (XIXA):
Figure imgf000073_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, Xe, and a are each as defined herein.
[00156] In another embodiment, provided herein is a compound of Formula (XXA):
Figure imgf000073_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X3, Z3, and a are each as defined herein.
[00157] In yet another embodiment, provided herein is a compound of Formula (XXIA):
Figure imgf000073_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3C, R4a, Rcl, Rc2, Rc4, Rc5, Ac, L, U5, V5, X5, Z5, and a are each as defined herein.
[00158] In yet another embodiment, provided herein is a compound of Formula (XXIIA):
Figure imgf000074_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re3, Ae, L, U5, V5, X3, Z3, and a are each as defined herein.
[00159] In still another embodiment, provided herein is a compound of Formula
(XXIII A):
Figure imgf000074_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00160] In one embodiment, provided herein is a compound of Formula (XIXB):
Figure imgf000075_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, Xe, and a are each as defined herein.
[00161] In another embodiment, provided herein is a compound of Formula (XXB):
Figure imgf000075_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00162] In yet another embodiment, provided herein is a compound of Formula (XXIB):
Figure imgf000076_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00163] In yet another embodiment, provided herein is a compound of Formula (XXIIB):
Figure imgf000076_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re4, Re5, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00164] In still another embodiment, provided herein is a compound of Formula (XXIIIB):
Figure imgf000077_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re2, Re5, Re6, Ae, L, U5, V5, X5, Z5, and a are each as defined herein.
[00165] In one embodiment, provided herein is a compound of Formula (XXIVA):
Figure imgf000077_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z5, Xe, a, and n are each as defined herein.
[00166] In another embodiment, provided herein is a compound of Formula (XXV A):
Figure imgf000077_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U3, V5, X5, Z5, a, and n are each as defined herein.
[00167] In yet another embodiment, provided herein is a compound of Formula (XXVIA):
Figure imgf000078_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00168] In yet another embodiment, provided herein is a compound of Formula
(XXVIIA):
Figure imgf000078_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U3, V3, X5, Z5, a, and n are each as defined herein.
[00169] In still another embodiment, provided herein is a compound of Formula (XXVIII A):
Figure imgf000079_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z3, a, and n are each as defined herein.
[00170] In one embodiment, provided herein is a compound of Formula (XXIVB):
Figure imgf000079_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z3, Xe, a, and n are each as defined herein.
[00171] In another embodiment, provided herein is a compound of Formula (XXVB):
Figure imgf000080_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00172] In yet another embodiment, provided herein is a compound of Formula (XXVIB):
Figure imgf000080_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00173] In yet another embodiment, provided herein is a compound of Formula
(XXVIIB):
Figure imgf000081_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00174] In still another embodiment, provided herein is a compound of Formula (XXVIIIB):
Figure imgf000081_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z5, a, and n are each as defined herein.
[00175] In one embodiment, provided herein is a compound of Formula (XXIXA):
Figure imgf000082_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X?, Z5, Xe, a, and n are each as defined herein.
[00176] In another embodiment, provided herein is a compound of Formula (XXXA):
Figure imgf000082_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00177] In yet another embodiment, provided herein is a compound of Formula (XXXIA):
Figure imgf000082_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U3, V5, X5, Z5, a, and n are each as defined herein.
[00178] In yet another embodiment, provided herein is a compound of Formula
(XXXIIA):
Figure imgf000083_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00179] In still another embodiment, provided herein is a compound of Formula (XXXIIIA):
Figure imgf000083_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z3, a, and n are each as defined herein. [00180] In one embodiment, provided herein is a compound of Formula (XXIXB):
Figure imgf000084_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re2, Re3, Ae, L, U5, V5, X3, Z5, Xe, a, and n are each as defined herein.
[00181] In another embodiment, provided herein is a compound of Formula (XXXB):
Figure imgf000084_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00182] In yet another embodiment, provided herein is a compound of Formula (XXXIB):
Figure imgf000085_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00183] In yet another embodiment, provided herein is a compound of Formula
(XXXIIB):
Figure imgf000085_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3e, R3d, R3e, R4a, Re1, Re2, Re3, Ae, L, U5, V5, X5, Z5, a, and n are each as defined herein.
[00184] In still another embodiment, provided herein is a compound of Formula (XXXIIIB):
Figure imgf000086_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R1, R4, R2a, R3a, R3b, R3C, R3d, R3e, R4a, Re2, Re3, Ae, L, L , V2, X5, Z5, a, and n are each as defined herein.
[00185] In certain embodiments, in any one of the formulae described herein, R1 is hydrogen. In certain embodiments, in any one of the formulae described herein, R1 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1 is methyl. In certain embodiments, in any one of the formulae described herein, R1 is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1 is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1 is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R1 is heterocyclyl, optionally substituted with one or more substituents Q.
[00186] In certain embodiments, in any one of the formulae described herein, R4 is deuterium. In certain embodiments, in any one of the formulae described herein, R4 is cyano. In certain embodiments, in any one of the formulae described herein, R4 is halo. In certain embodiments, in any one of the formulae described herein, each R4 is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R4 is nitro. In certain embodiments, in any one of the formulae described herein, each R4 is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4 is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4 is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4 is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4 is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4 is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4 is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4 is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R4 is independently heterocyclyl, optionally substituted with one or more substituents Q.
[00187] In certain embodiments, in any one of the formulae described herein, each R4 is independently -C(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -C(O)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -C(NR1 a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -C(S)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -C(S)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OC(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OC(O)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OC(O)SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OC(S)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OC(S)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OS(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OS(O)2R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1 aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1 aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -NR1aS(0)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -S(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -S(O)2R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R4 is independently -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00188] In certain embodiments, in any one of the formulae described herein, R5 is hydrogen. In certain embodiments, in any one of the formulae described herein, R5 is deuterium. In certain embodiments, in any one of the formulae described herein, R? is cyano. In certain embodiments, in any one of the formulae described herein, each R is independently halo. In certain embodiments, in any one of the formulae described herein, each R5 is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R5 is fluoro. In certain embodiments, in any one of the formulae described herein, R5 is nitro. In certain embodiments, in any one of the formulae described herein, each R5 is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R5 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5 is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5 is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5 is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5 is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5 is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5 is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5 is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R5 is independently heterocyclyl, optionally substituted with one or more substituents Q.
[00189] In certain embodiments, in any one of the formulae described herein, each R5 is independently -C(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -C(O)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R3 is independently -C(O)SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R3 is independently -C(S)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -C(S)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R3 is independently -OC(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OC(O)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OC(O)SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OC(S)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OC(S)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OS(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OS(O)2R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R3 is independently -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1 aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1 aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1 aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R is independently -NR1 aC(S)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1 aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R? is independently -NR1 aS(0)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -NR1aS(O)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -S(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -S(O)2R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R5 is independently -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00190] In certain embodiments, in any one of the formulae described herein, R6 is deuterium. In certain embodiments, in any one of the formulae described herein, R6 is cyano. In certain embodiments, in any one of the formulae described herein, each R6 is independently halo. In certain embodiments, in any one of the formulae described herein, each R6 is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R6 is fluoro. In certain embodiments, in any one of the formulae described herein, R6 is nitro. In certain embodiments, in any one of the formulae described herein, each R6 is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6 is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6 is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6 is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6 is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6 is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6 is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6 is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each R6 is independently heterocyclyl, optionally substituted with one or more substituents Q.
[00191] In certain embodiments, in any one of the formulae described herein, each R6 is independently -C(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -C(O)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -C(O)SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -C(S)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -C(S)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -C(S)NR1 bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OC(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OC(O)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OC(O)SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OC(S)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OC(S)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OS(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OS(O)2R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aC(S)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aS(0)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -NR1aS(O)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -SR1a, wherein R,a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -S(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -S(O)2R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each R6 is independently -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00192] In certain embodiments, in any one of the formulae described herein, R2a is hydrogen. In certain embodiments, in any one of the formulae described herein, R2a is deuterium. In certain embodiments, in any one of the formulae described herein, R2a is halo. In certain embodiments, in any one of the formulae described herein, R2a is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is methyl. In certain embodiments, in any one of the formulae described herein, R2a is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R2a is heterocyclyl, optionally substituted with one or more substituents Q.
[00193] In certain embodiments, in any one of the formulae described herein, R3a is hydrogen. In certain embodiments, in any one of the formulae described herein, R3a is deuterium. In certain embodiments, in any one of the formulae described herein, R3a is cyano. In certain embodiments, in any one of the formulae described herein, R3a is halo. In certain embodiments, in any one of the formulae described herein, R3a is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3a is fluoro. In certain embodiments, in any one of the formulae described herein, R3a is nitro.
[00194] In certain embodiments, in any one of the formulae described herein, R3a is C1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is methyl. In certain embodiments, in any one of the formulae described herein, R3a is C1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3a is heterocyclyl, optionally substituted with one or more substituents Q.
[00195] In certain embodiments, in any one of the formulae described herein, R3a is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -NR1 aS(0)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00196] In certain embodiments, in any one of the formulae described herein, R3a is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3a is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3a is hydrogen, fluoro, chloro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R3a is hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R3a is hydrogen. In certain embodiments, in any one of the formulae described herein, R3a is fluoro. In certain embodiments, in any one of the formulae described herein, R3a is methyl.
[00197] In certain embodiments, in any one of the formulae described herein, R3b is hydrogen. In certain embodiments, in any one of the formulae described herein, R3b is deuterium. In certain embodiments, in any one of the formulae described herein, R3b is cyano. In certain embodiments, in any one of the formulae described herein, R3b is halo. In certain embodiments, in any one of the formulae described herein, R3b is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3b is fluoro. In certain embodiments, in any one of the formulae described herein, R3b is nitro.
[00198] In certain embodiments, in any one of the formulae described herein, R3b is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is difluoromethyl, trifluoromethyl, or 1 , 1 -difluoro-2-hydroxy ethyl. In certain embodiments, in any one of the formulae described herein, R3b is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3b is heterocyclyl, optionally substituted with one or more substituents Q.
[00199] In certain embodiments, in any one of the formulae described herein, R3b is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is amino. In certain embodiments, in any one of the formulae described herein, R3b is -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1 aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1 aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1aS(O)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -S(O)NR1 bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00200] In certain embodiments, in any one of the formulae described herein, R3b is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3b is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoro- methyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3b is hydrogen, cyano, fluoro, chloro, bromo, methyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoro- methyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, hydroxyl, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3b is cyano, fluoro, nitro, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3b is cyano, fluoro, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3b is cyano. In certain embodiments, in any one of the formulae described herein, R3b is fluoro. In certain embodiments, in any one of the formulae described herein, R3b is difluoromethyl. In certain embodiments, in any one of the formulae described herein, R3b is trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R3b is amino.
[00201] In certain embodiments, in any one of the formulae described herein, R3c is hydrogen. In certain embodiments, in any one of the formulae described herein, R3c is deuterium. In certain embodiments, in any one of the formulae described herein, R3c is cyano. In certain embodiments, in any one of the formulae described herein, R3c is halo. In certain embodiments, in any one of the formulae described herein, R3c is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3c is fluoro. In certain embodiments, in any one of the formulae described herein, R3c is nitro. [00202] In certain embodiments, in any one of the formulae described herein, R3c is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3c is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3c is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3c is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3c is C6-i4 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3c is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3c is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3c is heterocyclyl, optionally substituted with one or more substituents Q.
[00203] In certain embodiments, in any one of the formulae described herein, R3e is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3C is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00204] In certain embodiments, in any one of the formulae described herein, R3e is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethyl-phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3c is hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R3c is hydrogen.
[00205] In certain embodiments, in any one of the formulae described herein, R3d is hydrogen. In certain embodiments, in any one of the formulae described herein, R3d is deuterium. In certain embodiments, in any one of the formulae described herein, R3d is cyano. In certain embodiments, in any one of the formulae described herein, R3d is halo. In certain embodiments, in any one of the formulae described herein, R3d is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3d is fluoro. In certain embodiments, in any one of the formulae described herein, R3d is nitro.
[00206] In certain embodiments, in any one of the formulae described herein, R3d is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is difluoromethyl, trifluoromethyl, or 1 , 1 -difluoro-2-hydroxy ethyl. In certain embodiments, in any one of the formulae described herein, R3d is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is C6-i4 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3d is heterocyclyl, optionally substituted with one or more substituents Q.
[00207] In certain embodiments, in any one of the formulae described herein, R3d is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is amino. In certain embodiments, in any one of the formulae described herein, R3d is -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1 aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1aS(O)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -S(O)NR1 bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00208] In certain embodiments, in any one of the formulae described herein, R3d is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3d is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3d is hydrogen, cyano, fluoro, chloro, bromo, methyl, di fluoromethyl, trifluoromethyl, l-cyano-1,1 -difluoro- methyl, 1 , 1 -difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, hydroxyl, amino, or methyl sulfonyl. In certain embodiments, in any one of the formulae described herein, R3d is cyano, fluoro, nitro, difluoromethyl, trifluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3d is cyano, fluoro, difluoromethyl, tri fluoromethyl, or amino. In certain embodiments, in any one of the formulae described herein, R3d is cyano. In certain embodiments, in any one of the formulae described herein, R3d is fluoro. In certain embodiments, in any one of the formulae described herein, R3d is difluoromethyl. In certain embodiments, in any one of the formulae described herein, R3d is trifluoromethyl. In certain embodiments, in any one of the formulae described herein, R3d is amino.
[00209] In certain embodiments, in any one of the formulae described herein, R3e is hydrogen. In certain embodiments, in any one of the formulae described herein, R3e is deuterium. In certain embodiments, in any one of the formulae described herein, R3e is cyano. In certain embodiments, in any one of the formulae described herein, R3c is halo. In certain embodiments, in any one of the formulae described herein, R3e is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R3e is fluoro. In certain embodiments, in any one of the formulae described herein, R3e is nitro.
[00210] In certain embodiments, in any one of the formulae described herein, R3e is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is methyl. In certain embodiments, in any one of the formulae described herein, R3e is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R3e is heterocyclyl, optionally substituted with one or more substituents Q.
[00211] In certain embodiments, in any one of the formulae described herein, R3e is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(NR1a)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OC(S)NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3c is -NR1aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00212] In certain embodiments, in any one of the formulae described herein, R3e is (i) hydrogen, cyano, or halo; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a, wherein each R1a, Rlb, and R1c is as defined herein. In certain embodiments, in any one of the formulae described herein, R3e is hydrogen, cyano, fluoro, chloro, bromo, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1 -cyano- 1,1 -difluoromethyl, l,l-difluoro-2-hydroxy ethyl, l,l-difluoro-2-hydroxy-2- methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methyl- aminomethylphenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl. In certain embodiments, in any one of the formulae described herein, R3e is hydrogen, fluoro, chloro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, or methoxy. In certain embodiments, in any one of the formulae described herein, R3e is hydrogen, fluoro, or methyl. In certain embodiments, in any one of the formulae described herein, R3e is hydrogen. In certain embodiments, in any one of the formulae described herein, R3e is fluoro. In certain embodiments, in any one of the formulae described herein, R3e is methyl.
[00213] In certain embodiments, in any one of the formulae described herein, R4a is hydrogen. In certain embodiments, in any one of the formulae described herein, R4a is deuterium. In certain embodiments, in any one of the formulae described herein, R4a is cyano. In certain embodiments, in any one of the formulae described herein, R4a is halo. In certain embodiments, in any one of the formulae described herein, R4a is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R4a is nitro. In certain embodiments, in any one of the formulae described herein, R4a is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4a is heterocyclyl, optionally substituted with one or more substituents Q.
[00214] In certain embodiments, in any one of the formulae described herein, R4a is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -C(S)R1a, wherein
- I l l - R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aS(0)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aS(O)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -NR1 aS(0)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4a is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00215] In certain embodiments, in any one of the formulae described herein, R4b is hydrogen. In certain embodiments, in any one of the formulae described herein, R4b is deuterium. In certain embodiments, in any one of the formulae described herein, R4b is cyano. In certain embodiments, in any one of the formulae described herein, R4b is halo. In certain embodiments, in any one of the formulae described herein, R4b is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R4b is nitro. In certain embodiments, in any one of the formulae described herein, R4b is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R4b is heterocyclyl, optionally substituted with one or more substituents Q.
[00216] In certain embodiments, in any one of the formulae described herein, R4b is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1 aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1aS(O)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -NR1aS(0)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R4b is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00217] In certain embodiments, in any one of the formulae described herein, R6a is hydrogen. In certain embodiments, in any one of the formulae described herein, R6a is deuterium. In certain embodiments, in any one of the formulae described herein, R6a is cyano. In certain embodiments, in any one of the formulae described herein, R6a is halo. In certain embodiments, in any one of the formulae described herein, R6a is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R6a is fluoro. In certain embodiments, in any one of the formulae described herein, R6a is nitro. In certain embodiments, in any one of the formulae described herein, R6a is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6a is heterocyclyl, optionally substituted with one or more substituents Q.
[00218] In certain embodiments, in any one of the formulae described herein, R6a is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OC(NR1a)NR1 bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OC(S)NR1bR1c, wherein R1b and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 aC(NR1 d)NR1 bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 aS(0)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -NR1 aS(0)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6a is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00219] In certain embodiments, in any one of the formulae described herein, R6b is hydrogen. In certain embodiments, in any one of the formulae described herein, R6b is deuterium. In certain embodiments, in any one of the formulae described herein, R6b is cyano. In certain embodiments, in any one of the formulae described herein, R6b is halo. In certain embodiments, in any one of the formulae described herein, R6b is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, R6b is fluoro. In certain embodiments, in any one of the formulae described herein, R6b is nitro. In certain embodiments, in any one of the formulae described herein, R6b is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, R6b is heterocyclyl, optionally substituted with one or more substituents Q.
[00220] In certain embodiments, in any one of the formulae described herein, R6b is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1 aC(NR1 d)NR1bR1c, wherein R1a, R1b, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1 aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1aS(O)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -S(O)NR1 bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, R6b is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00221] In certain embodiments, in any one of the formulae described herein, Re1 is hydrogen. In certain embodiments, in any one of the formulae described herein, Re1 is deuterium. In certain embodiments, in any one of the formulae described herein, Re1 is halo. In certain embodiments, in any one of the formulae described herein, Re1 is fluoro. In certain embodiments, in any one of the formulae described herein, Re1 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re1 is methyl.
[00222] In certain embodiments, in any one of the formulae described herein, Re2 is hydrogen. In certain embodiments, in any one of the formulae described herein, Re2 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re2 is (pivaloyloxy )methyl, valyloxymethyl, or ((di-tert- butoxyphosphoryl)oxy)methyl.
[00223] In certain embodiments, in any one of the formulae described herein, Re3 is deuterium. In certain embodiments, in any one of the formulae described herein, Re3 is cyano. In certain embodiments, in any one of the formulae described herein, Re3 is independently halo. In certain embodiments, in any one of the formulae described herein, each Re3 is independently fluoro or chloro. In certain embodiments, in any one of the formulae described herein, Re3 is nitro. In certain embodiments, in any one of the formulae described herein, each Re3 is independently Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re3 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3 is independently Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3 is independently C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3 is independently C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3 is independently C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Rc3 is independently C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3 is independently C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3 is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, each Re3 is independently heterocyclyl, optionally substituted with one or more substituents Q.
[00224] In certain embodiments, in any one of the formulae described herein, each Re3 is independently -C(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -C(O)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -C(O)SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -C(S)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -C(S)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OC(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OC(O)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OC(O)SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Rc3 is independently -OC(S)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OC(S)OR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OS(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OS(O)2R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -OS(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aC(iNR1d)NR1bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aC(S)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aS(O)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Rc3 is independently -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -NR1 aS(O)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -SR1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -S(O)R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -S(O)2R1a, wherein R1a is independently as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, each Re3 is independently -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00225] In certain embodiments, in any one of the formulae described herein, Re4 is hydrogen. In certain embodiments, in any one of the formulae described herein, Re4 is deuterium. In certain embodiments, in any one of the formulae described herein, Re4 is cyano. In certain embodiments, in any one of the formulae described herein, Re4 is halo. In certain embodiments, in any one of the formulae described herein, Re4 is fluoro or chloro. In certain embodiments, in any one of the formulae described herein, Re4 is nitro. In certain embodiments, in any one of the formulae described herein, Re4 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is C?-i5 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re4 is heterocyclyl, optionally substituted with one or more substituents Q.
[00226] In certain embodiments, in any one of the formulae described herein, Re4 is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OC(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OC(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OC(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OC(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OC(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OC(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OC(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OS(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OS(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -OS(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -0S(0)2NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Rc4 is -NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aC(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1aC(O)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aC(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aC(O)SR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aC(NR1 d)NR1bR1c, wherein R1a, Rlb, R1c, and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aC(S)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1aC(S)OR1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aC(S)NR1bR1c, wherein R1a, R1b, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1aS(O)R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aS(0)2R1d, wherein R1a and R1d are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aS(O)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -NR1 aS(0)2NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -S(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re4 is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00227] In certain embodiments, in any one of the formulae described herein, Re5 is hydrogen. In certain embodiments, in any one of the formulae described herein, Re5 is Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5 is Ci-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5 is C2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5 is C2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5 is C3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5 is C6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5 is C7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re3 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Re5 is heterocyclyl, optionally substituted with one or more substituents Q.
[00228] In certain embodiments, in any one of the formulae described herein, Re5 is -C(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -C(O)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -C(O)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -C(O)SR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -C(NR1a)NR1bR1c, wherein R1a, Rlb, and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -C(S)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re? is -C(S)OR1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -C(S)NR1bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -S(O)R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -S(O)2R1a, wherein R1a is as defined herein. In certain embodiments, in any one of the formulae described herein, Re? is -S(O)NR1 bR1c, wherein Rlb and R1c are each as defined herein. In certain embodiments, in any one of the formulae described herein, Re5 is -S(O)2NR1bR1c, wherein Rlb and R1c are each as defined herein.
[00229] In certain embodiments, in any one of the formulae described herein, Ae is a bond. In certain embodiments, in any one of the formulae described herein, Ae is C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is monocyclic C3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is bicyclic C4-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is bridged, fused, or spiro C4-10 cycloalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is C6-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is 6- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is spiro heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Ae is piperidindiyl, piperazindiyl, or 8-azabicyclo[3.2.1]octandiyl, each optionally substituted with one or more substituents Q. In yet another embodiment, in any one of the formulae described herein, Ae is piperidin-l,4-diyl, piperazin- 1,4-diyl, or 8-azabicyclo- [3.2.1 ]octan-3,8-diyl, each optionally substituted with one or more substituents Q.
[00230] In certain embodiments, in any one of the formulae described herein, L is Ci-6 alkylene or C7-14 arylene, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is C1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl or ethane- 1 ,2-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is methanediyl. In certain embodiments, in any one of the formulae described herein, L is ethane- 1 ,2-diyl. In certain embodiments, in any one of the formulae described herein, L is C7-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is monocyclic C7-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is phendiylmethandiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is phen-l,3-diylmethandiyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, L is -C(O)-.
[00231] In certain embodiments, in any one of the formulae described herein, L is a linker having the structure of -Zk-(Rk-Zk)z- wherein: each Rk is independently C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Zk is independently a bond, -C(O)-, -C(O)O- -C(O)NR1 b-, -C(O)S- C(NR1a)NR1b , C(S) , -C(S)O , C(S)NR1b , O , OC(O)O , OC(O)NR1b , OC(O)S , -OC(NR1a)NR1b-, -OC(S)O-, -OC(S)NR1b- -OS(O)-, -OS(O)2-, -OS(O)NR1 b- -OS(O)2NR1b- -NR1b-, -NR1 aC(O)NR1b- -NR1aC(O)S-, -NR1 aC(NR1d)NR1b- -NR1 aC(S)NR1b-, -NR1aS(O)NR1b-, -NR1aS(O)2NR1b-, -S-, -S(O)-, -S(O)2-, -S(O)NR1b-, or -S(O)2NR1b-; where each R1a, Rlb, and R1d is as defined herein; and z is an integer of 0, 1, 2, 3, 4, or 5.
[00232] In certain embodiments, in any one of the formulae described herein, each Rk is independently Ci-6 alkylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each Zk is independently a bond, -C(O)-, -C(O)NR1b-, -C(NR1 a)NR1b-, -O-, -OC(O)NR1b-, -NR1 b- -NR1 aC(O)NR1b-, -NR1 aC(NR1 d)NR1b-, -NR1 aS(O)NR1b-, -NR1 aS(O)2NR1b-, -S-, -S(O)- -S(O)2-, -S(O)NR1b-, or -S(O)2NR1b-; and z is an integer of 0, 1, 2, or 3; where each R1a, Rlb, and R1d is as defined herein.
[00233] In certain embodiments, in any one of the formulae described herein, each Rk is independently C1-6 alkylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each Zk is independently a bond, -C(O)-, -C(O)NR1b-, -O-, -OC(O)NR1 b-, -NR1 b-, -NR1aC(O)NR1b- -NR1 aC(NR1 d)NR1b-, or -S-; and z is an integer of 0, 1, 2, or 3; where each R1a, R1b, and R1d is as defined herein.
[00234] In certain embodiments, in any one of the formulae described herein, each Rk is independently methanediyl, ethanediyl, propanediyl, butanediyl, pentanediyl, hexanediyl, ethynediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl, phendiyl, pyrazoldiyl, imidazoldiyl, tetrazoldiyl, pyrimidindiyl, azetidindiyl, 1,3-dioxandiyl, piperazindiyl, piperidindiyl, or 3,9-diazaspiro[5.5]undecanediyl, each optionally substituted with one or more substituents Q; each Zk is independently a bond, -C(O)-, -C(O)O-, -C(O)NH-, -OC(O)NH- -O-, -NH-, -N(CH3)-, -NHC(O)NH-, or -S-; and z is an integer of 0, 1, 2, or 3.
[00235] In certain embodiments, in any one of the formulae described herein, each Rk is independently methanediyl, ethane- 1,2-diyl, propane- 1,3 -diyl, butane- 1,4-diyl, pentane- 1,5-diyl, hexane-l,6-diyl, ethyne- 1,2-diyl, cyclobutane- 1,1 -diyl, cyclobutane-l,3-diyl, cyclopentane- 1,3- diyl, cyclohexane-l,3-diyl, cyclohexane- 1,4-diyl, phen-l,3-diyl, phen- 1,4-diyl, pyrazol- 1,3 -diyl, pyrazol- 1,4-diyl, imidazol-l,4-diyl, 1,2, 3 -triazol- 1,4-diyl, pyrimidin-2,4-diyl, pyrimidin-2,5-diyl, pyrazolidin-l,3-diyl, pyrazolidin- 1,4-diyl, azetidin-l,3-diyl, l,3-dioxan-2,5-diyl, piperazin- 1,4- diyl, piperi din- 1,3 -diyl, or piperi din- 1,4-diyl, each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; each Zk is independently a bond, -C(O)-, -C(O)O- -C(0)NH-, -OC(O)NH-, -O-, -NH-, -N(CH3)-, -NHC(0)NH- or -S-; and z is an integer of 0, 1, 2, or 3.
[00236] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000132_0001
wherein each Ak is independently a bond, -O-, -NH-, or -N(CHs)-.
[00237] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000132_0002
wherein each Ak is independently a bond, -O-, -NH-, or -N(CHs)-.
[00238] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000132_0003
wherein each Ak is independently a bond, -O-, -NH-, or -N(CH3)-.
[00239] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000132_0004
wherein each Ak is independently a bond, -O-, -NH-, or -N(CH?)-; and wherein each amino (NH) group is optionally substituted with methyl.
[00240] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000132_0005
Figure imgf000133_0001
wherein each Ak is independently a bond, -O-, -NH-, or -N(CHs)-; and wherein each amino
(NH) group is optionally substituted with methyl.
[00241] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000133_0002
wherein each Ak is independently a bond, -O-, -NH-, or -N(CHa)-; and wherein each amino group (NH) is optionally substituted with methyl.
[00242] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000133_0003
wherein each Ak is independently a bond, -O-, -NH- or -N(CHs)-.
[00243] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000133_0004
Figure imgf000134_0001
wherein each Ak is independently a bond, -O-, -NH-, or -N(CHs)-; and wherein each amino group (NH) is optionally substituted with methyl.
[00244] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000134_0002
wherein each Ak is independently a bond, -O-, -NH-, or -N(CH3)-; and wherein each amino group (NH) is optionally substituted with methyl.
[00245] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000135_0001
wherein each Ak is independently a bond, -O-, -NH-, or -N(CH3)-.
[00246] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000135_0002
wherein each Ak is independently a bond, -O-, -NH-, or -N(CHa)-; and wherein each amino group (NH) is optionally substituted with methyl. [00247] In certain embodiments, in any one of the formulae described herein, L is:
Figure imgf000136_0001
wherein each Ak is independently a bond, -O-, -NH-, or -N(CHs)-.
[00248] In certain embodiments, in any one of the formulae described herein, U5 is -C(R5)=, wherein R5 is as defined herein. In certain embodiments, in any one of the formulae described herein, U5 is -C(R5)=, wherein R5 is (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, U5 is C(R5)=, wherein R5 is hydrogen, fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, U5 is -N=.
[00249] In certain embodiments, in any one of the formulae described herein, V5 is -C(R3)=, wherein R? is as defined herein. In certain embodiments, in any one of the formulae described herein, V5 is -C(R5)=, wherein R5 is (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, V5 is -C(R5)=, wherein R5 is hydrogen, fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, V5 is -N=.
[00250] In certain embodiments, in any one of the formulae described herein, X5 is -C(R5)=, wherein R5 is as defined herein. In certain embodiments, in any one of the formulae described herein, X5 is -C(R5)=, wherein R5 is (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, X5 is -C(R5)=, wherein R5 is hydrogen, fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, X5 is -N=.
[00251] In certain embodiments, in any one of the formulae described herein, Z5 is -C(R5)=, wherein R3 is as defined herein. In certain embodiments, in any one of the formulae described herein, Z5 is -C(R5)=, wherein R5 is (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, Z5 is -C(R5)=, wherein R5 is hydrogen, fluoro, chloro, or methyl. In certain embodiments, in any one of the formulae described herein, Z5 is -N=.
[00252] In one embodiment, in any one of the formulae described herein, U5, V5, X5, and Z5 are each independently -C(R5)=, wherein R5 is as defined herein. In another embodiment, in any one of the formulae described herein, U5 is -N=; and V5, X5, and Z5 are each independently -C(R5)=, wherein R5 is as defined herein. In yet another embodiment, in any one of the formulae described herein, U5, X5, and Z3 are each independently -C(R5)=, wherein R5 is as defined herein; and V5 is -N=. In yet another embodiment, in any one of the formulae described herein, U5, V5, and Z3 are each independently -C(R3)=, wherein R3 is as defined herein; and X5 is -N=. In still another embodiment, in any one of the formulae described herein, U5, V5, and X5 are each independently -C(R3)=, wherein R5 is as defined herein; and Z5 is -N=.
[00253] In one embodiment, in any one of the formulae described herein, U5, V5, X5, and Z3 are each independently -C(R5)=, wherein each R5 is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In another embodiment, in any one of the formulae described herein, U5 is -N=; and V5, X5, and Z5 are each independently -C(R5)=, wherein each R5 is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In yet another embodiment, in any one of the formulae described herein, U3, X5, and Z5 are each independently -C(R5)=, wherein each R3 is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q; and V5 is -N=. In yet another embodiment, in any one of the formulae described herein, L , V5, and Z5 are each independently -C(R5)=, wherein each R5 is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q. In still another embodiment, in any one of the formulae described herein, U5, V5, and X5 are each independently -C(R3)=, wherein each R3 is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q; and Z5 is -N=.
[00254] In one embodiment, in any one of the formulae described herein, U5, V5, X5, and Z5 are each independently -C(R5)=, wherein each R5 is independently hydrogen, fluoro, chloro, or methyl. In another embodiment, in any one of the formulae described herein, U5 is -N=; and V5, X5, and Z3 are each independently -C(R3)=, wherein each R5 is independently hydrogen, fluoro, chloro, or methyl. In yet another embodiment, in any one of the formulae described herein, U3, X5, and Z5 are each independently -C(R5)=, wherein each R5 is independently hydrogen, fluoro, chloro, or methyl; and V5 is -N=. In yet another embodiment, in any one of the formulae described herein, U5, V5, and Z5 are each independently -C(R5)=, wherein each R5 is independently hydrogen, fluoro, chloro, or methyl. In still another embodiment, in any one of the formulae described herein, U5, V3, and X5 are each independently -C(R5)=, wherein each R3 is independently hydrogen, fluoro, chloro, or methyl; and Z5 is -N=.
[00255] In certain embodiments, in any one of the formulae described herein, U6 is -C(Rb)2-, wherein each R6b is as defined herein. In certain embodiments, in any one of the formulae described herein, U6 is -C(H)(R6b)-, wherein R6b is as defined herein. In certain embodiments, in any one of the formulae described herein, U6 is -C(H2)-. In certain embodiments, in any one of the formulae described herein, U6 is -O-.
[00256] In certain embodiments, in any one of the formulae described herein, Xe is C(Re1), wherein Re1 is as defined herein. In certain embodiments, in any one of the formulae described herein, Xe is N.
[00257] In certain embodiments, in any one of the formulae described herein, Z is -Chhin certain embodiments, in any one of the formulae described herein, Z is -C(O)-. [00258] In certain embodiments, in any one of the formulae described herein, a is an integer of 0. In certain embodiments, in any one of the formulae described herein, a is an integer of 1. In certain embodiments, in any one of the formulae described herein, a is an integer of 2.
[00259] In certain embodiments, in any one of the formulae described herein, b is an integer of 0. In certain embodiments, in any one of the formulae described herein, b is an integer of 1. In certain embodiments, in any one of the formulae described herein, b is an integer of 2. In certain embodiments, in any one of the formulae described herein, b is an integer of 3. In certain embodiments, in any one of the formulae described herein, b is an integer of 4. In certain embodiments, in any one of the formulae described herein, b is an integer of 5. In certain embodiments, in any one of the formulae described herein, b is an integer of 6.
[00260] In certain embodiments, in any one of the formulae described herein, m is an integer of 0. In certain embodiments, in any one of the formulae described herein, m is an integer of 1. In certain embodiments, in any one of the formulae described herein, m is an integer of 2.
[00261] In certain embodiments, in any one of the formulae described herein, n is an integer of 0. In certain embodiments, in any one of the formulae described herein, n is an integer of 1 . In certain embodiments, in any one of the formulae described herein, n is an integer of 2. In certain embodiments, in any one of the formulae described herein, n is an integer of 3.
[00262] In certain embodiments, in any one of the formulae described herein, n is an integer of 1; and Re3 is (i) halo; or (ii) Ci-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, n is an integer of 1; and Re3 is (i) halo; or (ii) C1-6 alkyl or monocyclic C3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, n is an integer of 1; and Re3 is fluoro, chloro, methyl, difluoromethyl, trifluorom ethyl, or cyclopropyl. In certain embodiments, in any one of the formulae described herein, n is an integer of 2; and each Re3 is independently (i) halo; or (ii) C1-6 alkyl or C3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, n is an integer of 2; and each Re3 is independently (i) halo; or (ii) C1-6 alkyl or monocyclic C3-10 cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of the formulae described herein, n is an integer of 2; and each Re3 is independently fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, or cyclopropyl.
[00263] All combinations of the embodiments provided herein for the groups in the formulae described herein, including, e.g., R1, R3, R4, R5, R6, R2a, R2b, R3a, R3b, R3c, R3d, R3e, R4a, R4b, R6a, R6b, Re, Re1, Re2, Re3, Re4, Re5, A, Ae, L, U, V, X, Xe, Z, U5, V5, X5, Z5, U6, a, b, m, and n, are within the scope of this disclosure.
[00264] In one embodiment, provided herein is a compound of:
3-(5-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A001;
3-(5-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l -ox oisoindolin-2-yl)piperidine-2, 6-dione A002;
3 -(5 -( 1 -(3 -(4-(((R)- 1 -(3 -(difluorom ethyl )-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A003;
3-(5-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione A004; or
3 -(5 -( 1 -((5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)pyri din-3 -yl)methyl)piperidin-4-yl)-6-fluoro- 1-oxo- isoindolin-2-yl)piperidine-2, 6-dione A005; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00265] In another embodiment, provided herein is (R)-3-(6-(1-(3-(4-(((R)-1-(3-(difluoro- methyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4- yl)-5-fluoro-l-methyl-1H-indazol-3-yl)-3-methylpiperidine-2, 6-dione A051; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00266] In yet another embodiment, provided herein is a compound of
(R)- 1 -(6-( 1 -(5 -( 1 -(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-l/7-indazol-3-yl)dihydro- pyrimidine-2, 4(1H,3H)-dione A061; (R)-1-(6-(1-(5-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorophenethyl)piperidin-4-yl)-l -methyl- l/7-indazol-3-yl)- dihydropyrimidine-2,4((1H,3H)-)dione A062;
(R)- 1 -(6-( 1 -(5-(4-(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-5-fluoro-l -methyl- 1/7-indazol -3- yl)dihydropyrimidine-2, 4(1H,3H)-dione A063; or (R)-1-(6-(1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-5-fluoro-l-m ethyl- 1H-indazol-3-yl)dihydro- pyrimidine-2, 4(1H,3H)-dione A064; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00267] In yet another embodiment, provided herein is a compound of: (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione A101;
3 -(4-( 1 -( 5 -(4-(((R)- 1 -(3 -(difluorom ethyl )-2-fluorophenyl )ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2,6- dione A102; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3 -methyl- piperidine-2, 6-dione A103;
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3 -methylpiperidine- 2,6-dione A104;
(R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)- 3-methylpiperidine-2, 6-dione A105;
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione A106;
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3-methyl- piperidine-2, 6-dione A107;
(R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-< ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione A108;
(R)-3 -(3 -cyclopropyl-4-(l -(5-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A109; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-fi?]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3 -methyl- piperidine-2, 6-dione A110;
(R)-3 -(3 -cy clopropy l-4-( 1 -(3 -(4-(((R)- 1 -(3 -(diflu oromethy l)-2-fluoropheny 1)- ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A1li;
3-(4-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione A112; (R)-3-(3-chloro-4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-2-methylpyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A113;
(R)-3 -(3 -chloro-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny 1 )ethy 1 ) - amino)-2-methylpyrido[3,4-d ]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione A114; R)-3 -(4-( 1 -((5
Figure imgf000142_0001
1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-l -methyl -2-oxo-l,2-dihydropyridin-3-yl)methyl)piperidin- 4-yl)phenyl)-3 -methylpiperidine-2, 6-dione A115;
(R)-3 -(3 -(difluoromethyl)-4-( 1 -(3 -(4-( ((R)- 1 -(3 -(difluoromethyl )-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A116; (R)-3-(3-(difluoromethyl)-4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3 -methylpiperidine-2, 6-dione A117; (R) - 3 -(4 - ( 1 - (3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethy l)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione A118;
3-(4-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- di one A119;
3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)- piperidine-2, 6-dione A120;
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2,3-difluorophenyl)-3-methyl- piperidine-2, 6-dione A121;
(R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methyl-piperidine-2, 6-dione A122;
(R)-3 -(4-( 1 -(((S)- 1 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione A123; or
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-t/]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2-fluoro-3-methylphenyl)-3-methyl- piperidine-2, 6-dione A124; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00268] In yet another embodiment, provided herein is a compound of:
3 -(5-(4-(3 -(1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B001;
3 -(6-fluoro-5 -( 1 -(3 -(4-m ethyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione B002;
3-(5-(4-(3-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B003;
3 -(5-( 1 -(5-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-6-fluoro-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B004;
3-(5-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4- ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B005;
3-(5-(1-(5-(l -(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyri do[3,4-d ]pyridazin-7-yl)-2 -fluorobenzyl )piperidin-4-yl)-6-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione B006; or
3-(5-(1-(3-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B007; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00269] In yet another embodiment, provided herein is a compound of:
3 -( 1 -methyl-6-(4-(3 -(4-methyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)-17/-indazol-3-yl)piperidine-2,6- dione B051; 3-((17?)-1-((7-(4-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-1H-indazol-6-yl)- piperidin-l-yl)methyl)phenyl)piperazin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)- 2-methylbenzonitrile B052;
3 -(( 17?)- 1 -((7-(3 -((4-(3 -(2,6-dioxopiperidin-3 -yl)- 1 -methyl- 1H-indazol-6-yl)- piperi din- l-yl)methyl)phenyl)-4-methylpyrido[3,4-d ]pyridazin-l-yl)amino)ethyl)-2 -methylbenzonitrile B053;
3 -( 1 -methyl-7 -( 1 -(3 -(4-methyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6- dione B054;
3-(6-(1-(3-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-methyl-1H-indazol-3-yl)piperidine-2,6- dione B055;
3 -((17?)- 1 -((7-(3 -((4-(3 -(2,6-dioxopiperidin-3 -yl)- 1 -methyl- 1H-indazol-7-yl)- piperidin-l-yl)methyl)phenyl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methyl- benzonitrile B056;
3-(7-(1-(5-(l -(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-17/-indazol-3-yl)- piperidine-2, 6-dione B057; or (R) - 3 -(6 - ( 1 - ( 5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-1H-indazol-3-yl)-3- methylpiperidine-2, 6-dione B058; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00270] In yet another embodiment, provided herein is (R)-1-(6-(1-(5-(1-((1-(3- (difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methylpyrido[3,4-d ]pyridazin-7-yl)-2- fluorobenzyl)piperi din-4-yl)-l-methyl-1H-indazol-3-yl)dihydropyrimidine-2, 4(1H, 37/)-dione B091 ; or (R)- 1-(6-(1-(5-(l -(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)-amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorophenethyl)piperidin-4-yl)-l-methyl-1H-indazol-3- yl)-dihydropyrimidine-2, 4(1H, 3H)-dione B092; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00271] In yet another embodiment, provided herein is a compound of:
3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B101;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -amino-5 -(trifluoromethyl)phenyl)ethyl)amino)-4-methy 1- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B102;
3-(4-(1-(3-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)phenethyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B103;
3 -(4-(4-(3 -( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)phenethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B104;
3 -(4-(4-(3 -( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B105;
3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -amino-5 -(trifluorom ethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)- piperidine-2, 6-dione B106;
3-(4-(2-(5-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4--d]pyridazin-7-yl)-2-oxopyridin-l(2H)-yl)ethyl)phenyl)piperidine-2, 6-dione B107;
3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B108;
3 -(( 17?)- 1 -((7-(3 -((4-(4-(2,6-dioxopiperi din-3 -yl)phenyl)piperidin- 1 -yl)methyl)- phenyl)-4-methylpyrido[3,4-d ]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile B109;
3 -(4-( 1 -(3 -(4-m ethyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethyl)pheny l)ethyl)- amino)pyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B110;
3-(4-(1-(2-(5-(l -(((R)- 1 -(3 -amino-5 -(trifluorom ethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-oxopyridin-l(2H)-yl)ethyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione Bill;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-(/]pyridazin-7-yl)-5-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B112;
3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-4-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 13; 3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 14;
3 -(4-( 1 -(3 -( 1 - ( ((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 15;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)-5-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 16;
3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 17;
3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-4-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 18;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethy l)amino)-4-methy 1- pyrido[3,4-d ]pyridazin-7-yl)-2-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 19;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4-methyl- pyrido[3,4- ]pyridazin-7-yl)phenethyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B120;
3-(4-(1-(2-chloro-5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 4-methylpyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B121;
2-methyl-3-((R)-1-((4-methyl-7-(3-((4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)- phenyl)piperidin-l-yl)methyl)phenyl)pyrido[3,4--d]pyridazin-l-yl)amino)ethyl)benzonitrile B122; (R)-3-methyl-3-(4-(1-(3-(4-methyl-1-(((R)-1-(2-methyl-3-(trifluoromethyl)- phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B123;
2-methyl-3-((R)-1-((4-methyl-7-(3-((4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)- phenyl)piperidin-l-yl)methyl)phenyl)pyrido[3,4-7]pyridazin-l-yl)amino)ethyl)benzonitrile B124; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4- ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-2, 6-dione B125; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione B126; (R)-3-(4-(l -(5-(l -(((R)-l -(3-(difluoromethyl)-2-fluorophenyl)ethyl)arnino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B127; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B128; (R)-3 -(4-( 1 -(2-fluoro-5 -( 1 -(((R)- 1 -(3 -fluoro-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-2, 6-dione B129;
3 -(4-( 1 -(5-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2,6- dione B130;
3 -(4-( 1 -(5-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)piperidine-2, 6-dione B131;
3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)- piperidine-2, 6-dione B132;
(R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B133; (R) - 3 -(4 - ( 1 - ( 3 -( 1 - (((R) - 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-5-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B134; (R)-3 -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-4-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B135; (R)-3-(4-(1-(((R)-4-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B136; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2,6-dione B137; (R)-3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B138; (R) - 3 -( 4 - ( 1 - ( 5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B139; (R) - 3 -(4 - ( 1 - ( 5 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)- 1,2,3, 6-tetrahydropyridin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B140; (R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)furan-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B141;
(37?)-3-(4-(8-(((R)-4-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)arnino)- 4-methylpyrido[3,4-d ]pyridazin-7-yl)morpholin-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-3- methylphenyl)-3-methylpiperidine-2, 6-dione B142;
(3R)-3 -(4-(8-(5-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B143; (R)-3 -(4-( 1 -((5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)pyridin-3-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B144; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3- methylpiperidine-2, 6-dione B145; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione B146; (R)-3 -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3-methyl- piperidine-2, 6-dione B147;
(R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione B148;
(R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)thiophen-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B149; (R) - 3 -(4 - ( 1 - ( 5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3-methyl- piperidine-2, 6-dione B150; (R)-3 -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluorophenyl)-3-methylpiperidine- 2,6-dione B151; (R) - 3 -( 4 - ( 1 - ( 5 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzoyl)piperidin-4-yl)phenyl)-3-methylpiperidine-
2.6-dione B152;
((R) -3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl )amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl-
2.6-dioxopiperidin-l-yl)methyl pivalate B153;
3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione B154; (R) - 3 -(4 - ( 1 - ( (4 - ( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl )amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)pyridin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B155; (R)-3-(3-chloro-4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B156; (R)-3 -(3 -chloro-4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-4-methylpyrido[3,4-rZ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-
2.6-dione B157; (R)-3 -(3 -cy clopropy l-4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny 1)- ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione B158;
(R)-3 -(3 -cy clopropy l-4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(difluoromethy l)-2-fluorophenyl)- ethyl)amino)-4-methylpyrido[3,4-7]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B159;
(R)-3 -(4-( 1 -(((£)- 1 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl )amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B160;
(R)-3 -(4-( 1 -(5 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methylpiperidine-2, 6-dione B161;
(R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-2-methylphenyl)-3-methyl- piperidine-2, 6-dione B162; (R)-3 -(3 -(difluoromethyl)-4-( 1 -(5-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoro- phenyl)ethyl)amino)-4-methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3-methylpiperidine-2, 6-dione B163; (R)-3 -(3 -(difluoromethyl)-4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoro- phenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione B164; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione B165;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- dione B166; or
3 -(4-( 1 -(5-(l -(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine- 2,6-dione B167; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00272] In yet another embodiment, provided herein is (R)-1-(4-(1-(5-(1-((1-(3-(difluoro- methyl)-2-fhiorophenyl)ethyl)amino)-4-methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)- piperidin-4-yl)phenyl)dihydropyrimidine-2, 4(1/7, 3H)-dione B201; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00273] In still another embodiment, provided herein is a compound of:
(R)-3 -(4-( 1 -((6-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 1 - methylphthal azin-6-yl)pyri din-2 -yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C001;
(R)-3 -(4-( 1 -((2-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 1 - methylphthal azin-6-yl)pyri din-4-yl)methyl )piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C002; or
(R)-3 -(4-( 1 -((4-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethy l)amino)- 1 - methylphthal azin-6-yl)pyri din-2 -yl )methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C003; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00274] In certain embodiments, a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon-14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to, 15N for nitrogen; 17O or 18O for oxygen, and 34S, 35S, or 36S for sulfur.
[00275] In certain embodiments, a compound provided herein has an isotopic enrichment factor of no less than about 5, no less than about 10, no less than about 20, no less than about 50, no less than about 100, no less than about 200, no less than about 500, no less than about 1,000, no less than about 2,000, no less than about 5,000, or no less than about 10,000. In any events, however, an isotopic enrichment factor for a specified isotope is no greater than the maximum isotopic enrichment factor for the specified isotope, which is the isotopic enrichment factor when a compound at a given position is 100% enriched with the specified isotope. Thus, the maximum isotopic enrichment factor is different for different isotopes. The maximum isotopic enrichment factor is 6,410 for deuterium and 90 for carbon-13.
[00276] In certain embodiments, a compound provided herein has a deuterium enrichment factor of no less than about 64 (about 1% deuterium enrichment), no less than about 130 (about 2% deuterium enrichment), no less than about 320 (about 5% deuterium enrichment), no less than about 640 (about 10% deuterium enrichment), no less than about 1,300 (about 20% deuterium enrichment), no less than about 3,200 (about 50% deuterium enrichment), no less than about 4,800 (about 75% deuterium enrichment), no less than about 5,130 (about 80% deuterium enrichment), no less than about 5,450 (about 85% deuterium enrichment), no less than about 5,770 (about 90% deuterium enrichment), no less than about 6,090 (about 95% deuterium enrichment), no less than about 6,220 (about 97% deuterium enrichment), no less than about 6,280 (about 98% deuterium enrichment), no less than about 6,350 (about 99% deuterium enrichment), or no less than about 6,380 (about 99.5% deuterium enrichment). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments, at least one of the atoms of a compound provided herein, as specified as deuterium-enriched, has deuterium enrichment of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98%.
[00277] In certain embodiments, a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
[00278] The compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. Where a compound provided herein contains an alkenyl group, the compound may exist as one or mixture of geometric cisltrans (or ZIE) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
[00279] A compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (R) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its ( ) form. Conventional techniques for the preparation/isolation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
[00280] When a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1- 19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a hydrate.
[00281] Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(lS)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, a- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-l,5-disulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p- toluenesulfonic acid, undecylenic acid, and valeric acid.
[00282] Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, A'-m ethyl - glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, 7V-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)- 1,3 -propanediol, and tromethamine.
[00283] A compound provided herein may also be provided as a prodrug, which is a functional derivative of the compound and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis.
Pharmaceutical Compositions
[00284] In one embodiment, provided herein is a pharmaceutical composition, comprising a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.
[00285] The pharmaceutical composition provided herein can be formulated in various dosage forms, including, but not limited to, dosage forms for oral, parenteral, and topical administration. The pharmaceutical composition can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra, Modified- Release Drug Delivery Technology, 2nd ed.; Rathbone el al, Eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.
[00286] In one embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for oral administration. In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration. In still another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for topical administration.
[00287] The pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art.
Each unit-dose contains a predetermined quantity of an active ingredient(s) (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of a unit-dosage form include, but are not limited to, an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of a multiple-dosage form include, are not limited to, a vial, bottle of tablets or capsules, or bottle of pints or gallons.
[00288] The pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.
A. Oral Administration
[00289] The pharmaceutical composition provided herein for oral administration can be provided in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fdlers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
[00290] Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500®); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, Ghatti gum, mucilage of isabgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), VEEGUM®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); and microcrystalline celluloses, such as AVICEL® PH-101, AVICEL® PH-103, AVICEL® PH-105, and AVICEL® RC-581. Suitable fdlers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pre-gelatinized starch. The amount of a binder or filler in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical composition provided herein.
[00291] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. C6rtain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of a diluent in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
[00292] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cationexchange resins; alginic acid; gums, such as guar gum and VEEGUM® HV; citrus pulp; crosslinked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; crosslinked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as com starch, potato starch, tapioca starch, and pregelatinized starch; clays; and algins. The amount of a disintegrant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical composition provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
[00293] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; and silica or silica gels, such as AEROSIL® 200 and CAB-O-SIL®. The amount of a lubricant in the pharmaceutical composition provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
[00294] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O- SIL®, and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes. A color lake is a combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN* 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, VEEGUM®, acacia, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, and sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate. [00295] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.
[00296] The pharmaceutical composition provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredient(s) from the acidic environment of the stomach. Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
[00297] The tablet dosage forms can be prepared from an active ingredient(s) in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
[00298] The pharmaceutical composition provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient(s). The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient(s).
[00299] The pharmaceutical composition provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be measured conveniently for administration.
[00300] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient(s), and a dialkylated mono- or poly-alkylene glycol, including, 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350- dimethyl ether, polyethylene gly col-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
[00301] The pharmaceutical composition provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
[00302] The pharmaceutical composition provided herein for oral administration can be provided as non-efferve scent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non- effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
[00303] Coloring and flavoring agents can be used in all of the dosage forms described herein.
[00304] The pharmaceutical composition provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
B. Parenteral Administration
[00305] The pharmaceutical composition provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral administration, as used herein, include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrastemal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
[00306] The pharmaceutical composition provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, e.g., Remington: The Science and Practice of Pharmacy, supra.
[00307] The pharmaceutical composition provided herein for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
[00308] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer’s injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer’s injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and mediumchain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3 -butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, JV-methyl-2-pyrrolidone, A(A-dimethylacetamide, and dimethyl sulfoxide.
[00309] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e. ., benzethonium chloride), methyl - and propyl-parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including a- cyclodextrin, P-cyclodextrin, hydroxypropyl-P-cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether 7-P-cyclodextrin (CAPTISOL®).
[00310] When the pharmaceutical composition provided herein is formulated for multiple dosage administration, multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
[00311] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including a lyophilized powder and hypodermic tablet, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.
[00312] The pharmaceutical composition provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
[00313] The pharmaceutical composition provided herein for parenteral administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical composition provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient(s) in the pharmaceutical composition to diffuse through.
[00314] Suitable inner matrixes include, but are not limited to, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers (such as hydrogels of esters of acrylic and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.
[00315] Suitable outer polymeric membranes include, but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, poly dimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer.
C. Topical Administration
[00316] The pharmaceutical composition provided herein can be administered topically to the skin, orifices, or mucosa. The topical administration, as used herein, includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.
[00317] The pharmaceutical composition provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches. The topical formulations of the pharmaceutical composition provided herein can also comprise liposomes, micelles, microspheres, and nanosystems.
[00318] Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, nonaqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
[00319] The pharmaceutical composition can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ and BIOJECT™.
[00320] The pharmaceutical composition provided herein can be provided in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water- soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, e.g., Remington: The Science and Practice of Pharmacy, supra. These vehicles are emollient but generally require addition of antioxidants and preservatives.
[00321 ] Suitable cream base can be oil-in-water or water-in-oil. Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the “internal” phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
[00322] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
[00323] The pharmaceutical composition provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
[00324] Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices. Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with an active ingredient(s); and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and poly acrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
[00325] The pharmaceutical composition provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
[00326] The pharmaceutical composition provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical composition can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1, 1,2, 3, 3, 3- heptafluoropropane. The pharmaceutical composition can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops. For intranasal use, the powder can comprise a bioadhesive agent, including chitosan or cyclodextrin.
[00327] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of an active ingredient(s); a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
[00328] The pharmaceutical composition provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
[00329] Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical composition provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical composition provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
[00330] The pharmaceutical composition provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
D. Modified Release
[00331] The pharmaceutical composition provided herein can be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of an active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical composition in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphism of the active ingredient(s).
1. Matrix Controlled Release Devices
[00332] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated using a matrix-controlled release device known to those skilled in the art. See, e.g., Takada el al. in Encyclopedia of Controlled Drug Delivery, Mathiowitz Ed.; Wiley, 1999; Vol. 2.
[00333] In certain embodiments, the pharmaceutical composition provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
[00334] Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum Ghatti, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®); poly(2-hydroxyethyl- methacrylate); polylactides; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3 -hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride.
[00335] In certain embodiments, the pharmaceutical composition provided herein is formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylenevinyl acetate copolymers, ethyl ene/propylene copolymers, ethyl ene/ethyl acrylate copolymers, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
[00336] In a matrix-controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
[00337] The pharmaceutical composition provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
2. Osmotic Controlled Release Devices
[00338] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS). In general, such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core. The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
[00339] In addition to the active ingredient(s), the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents is water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.” Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
[00340] The other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.
[00341] Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM™ EZ can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
[00342] The core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
[00343] Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water- permeable and water-insoluble at physiologically relevant pHs or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00344] Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, poly vinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
[00345] The delivery port(s) on the semipermeable membrane can be formed post-coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698,220.
[00346] The total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
[00347] The pharmaceutical composition in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
[00348] The osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy, supra, Santus and Baker, J. Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma etal., J. Controlled Release, 2002, 79, 7-27.
[00349] In certain embodiments, the pharmaceutical composition provided herein is formulated as an AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers. See, e.g., U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
[00350] In certain embodiments, the pharmaceutical composition provided herein is formulated as an ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
3. Multiparticulate Controlled Release Devices
[00351] The pharmaceutical composition provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 pm to about 3 mm, about 50 pm to about 2.5 mm, or from about 100 pm to about 1 mm in diameter. Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and drygranulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, e.g. , Multiparticulate Oral Drug Delivery, Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Palletization Technology, Ghebre-Sellassie Eds.; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989.
[00352] Other excipients or carriers as described herein can be blended with the pharmaceutical composition to aid in processing and forming the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed as a capsule or a tablet.
4. Targeted Delivery
[00353] The pharmaceutical composition provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody -based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751 ; 6,071,495; 6,060,082; 6,048,736; 6,039,975;
6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.
Methods of Use
[00354] In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a son of sevenless homolog 1 (SCSI) in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00355] In certain embodiments, the disorder, disease, or condition mediated by an S0S1 is a proliferative disease.
[00356] In another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a RAS in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00357] In certain embodiments, the disorder, disease, or condition mediated by a RAS is a proliferative disease. In certain embodiments, the RAS is a KRAS. In certain embodiments, the RAS is a HRAS. In certain embodiments, the Ras is an NRAS.
[00358] In yet another embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g, a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00359] In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is colon cancer, colorectal cancer, lung cancer, or pancreatic cancer. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is an unresectable solid tumor. In certain embodiments, the cancer is a hematologic malignancy.
[00360] In certain embodiments, the cancer is refractory and/or relapsed. In certain embodiments, the cancer is refractory. In certain embodiments, the cancer is relapsed. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is unresectable. In certain embodiments, the cancer is metastatic.
[00361] In certain embodiments, the cancer is drug-resistant. In certain embodiment, the cancer is multidrug-resistant. In certain embodiments, the cancer is resistant to a chemotherapy. In certain embodiments, the cancer is resistant to an immunotherapy. In certain embodiments, the cancer is resistant to a standard therapy for the cancer.
[00362] In certain embodiments, the cancer bears a KRAS mutation. In certain embodiments, the cancer bears a KRAS mutation at the G12 or G13 position. In certain embodiments, the cancer bears a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the cancer bears a KRAS mutation of G12C. In certain embodiments, the cancer bears a KRAS mutation of G12D. In certain embodiments, the cancer bears a KRAS mutation of G12V. In certain embodiments, the cancer bears a KRAS mutation of G12A. In certain embodiments, the cancer bears a KRAS mutation of G12S. In certain embodiments, the cancer bears a KRAS mutation of G12R. In certain embodiments, the cancer bears a KRAS mutation at the G13 position. In certain embodiments, the cancer bears a KRAS mutation of G13D.
[00363] In certain embodiments, the cancer is a solid tumor with a KRAS mutation. In certain embodiments, the cancer is a solid tumor with a KRAS mutation at the G12 or G13 position. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12C. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12D. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12V. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12A. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12S. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G12R. In certain embodiments, the cancer is a solid tumor with a KRAS mutation at the G13 position. In certain embodiments, the cancer is a solid tumor with a KRAS mutation of G13D.
[00364] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
[00365] In certain embodiments, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 60 mg/kg/day, from about 0.1 to about 50 mg/kg/day, from about 0.1 to about 25 mg/kg/day, from about 0.1 to about 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1 to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day. In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 100 mg/kg/day. In another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 60 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0. 1 to about 50 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 25 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 20 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 15 mg/kg/day. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 10 mg/kg/day. In still another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 to about 5 mg/kg/day.
[00366] It is understood that the administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m2/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m2/day to given either the height or weight of a subject or both. For example, a dose of 1 mg/m2/day for a 65 kg human is approximately equal to 58 mg/kg/day.
[00367] Depending on the disorder, disease, or condition to be treated and the subject’s condition, a compound provided herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intraci sternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e. , transdermal or local) routes of administration. A compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for each route of administration.
[00368] In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered parenterally. In yet another embodiment, a compound provided herein is administered intravenously. In yet another embodiment, a compound provided herein is administered intramuscularly. In yet another embodiment, a compound provided herein is administered subcutaneously. In still another embodiment, a compound provided herein is administered topically.
[00369] A compound provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time. A compound provided herein can be administered repetitively, if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.
[00370] A compound provided herein can be administered once daily (QD) or divided into multiple daily doses such as twice daily (BID), and three times daily (TID). In addition, the administration can be continuous, i.e., every day, or intermittently. The term “intermittent” or “intermittently” as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound provided herein is administration for one to six days per week, administration in cycles (e.g, daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
[00371] In certain embodiments, a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improves the efficacy of the treatment.
[00372] A compound provided herein can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of a condition, disorder, or disease described herein.
[00373] As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.
[00374] The route of administration of a compound provided herein is independent of the route of administration of a second therapy. In one embodiment, a compound provided herein is administered orally. In another embodiment, a compound provided herein is administered intravenously. Thus, in accordance with these embodiments, a compound provided herein is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, a compound provided herein and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, a compound provided herein is administered by one mode of administration, e.g., by IV, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., orally.
[00375] In one embodiment, provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00376] In certain embodiments, the cell is a cancerous cell. In certain embodiments, the cell is a human cell. In certain embodiments, the cell is a human cancerous cell.
[00377] In certain embodiments, the cell is a cell of colon cancer, colorectal cancer, lung cancer, or pancreatic cancer. In certain embodiments, the cell is a cell of non-small cell lung cancer (NSCLC).
[00378] In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation at the G12 or G13 position. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12C. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12D. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12V. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12A. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12S. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G12R. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation at the G13 position. In certain embodiments, the cell is a cancerous cell bearing a KRAS mutation of G13D.
[00379] In another embodiment, provided herein is a method of inducing degradation of an S0S1, comprising contacting the S0S1 with a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
[00380] A compound provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos.
5,525,907; 5,052,558; and 5,055,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
[00381] In certain embodiments, provided herein is a kit which, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein.
[00382] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
[00383] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, water for injection USP, sodium chloride injection, Ringer’s injection, dextrose injection, dextrose and sodium chloride injection, and lactated Ringer’s injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[00384] The disclosure will be further understood by the following non-limiting examples.
EXAMPLES
[00385] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); p.L (microliters); mM (millimolar); pM (micromolar); mmol (millimoles); min (minute or minutes); h (hour or hours); AcO or OAc (acetate); Bn (benzyl); Boc (tert-butoxycarbonyl); /BuOK (potassium ter /-but oxi de); DIEA or DIPEA (A, A-di isopropyl ethyl amine); Et (ethyl); LDA (lithium diisopropylamide); Ms (mesyl); PMB (/i-m ethoxybenzyl); Pd(dppf)Ch (1,1’- bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex); TFA (trifluoroacetic acid); TfOH (triflic acid); LCMS (liquid chromatography-mass spectrometry); MS (mass spectrometry); NMR (nuclear magnetic resonance); prep-HPLC (preparative high performance liquid chromatography); and SFC (supercritical fluid chromatography).
[00386] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees C6ntigrade). All reactions are conducted at room temperature unless otherwise specified. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure.
Example 1 Preparation of 3-(5-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4--d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A001
Figure imgf000183_0001
[00387] Compound A001 was prepared as shown in Scheme 1. 1H NMR (400 MHz, DMSO-tC) δ 10 .97 (br s, 1H), 9.08 (s, 1H), 8.90 (br d, J= 6.8 Hz, 1H), 8.84 (s, 1H), 8.34-8.23 (m, 1H), 8.14 (br s, 1H), 7.72 (br t, J= 7.2 Hz, 1H), 7.68-7.60 (m, 1H), 7.59-7.47 (m, 2H), 7.43- 7.36 (m, 2H), 7.33-7.08 (m, 2H), 5.89-5.75 (m, 1H), 5.09 (br dd, J= 5.2 13.2 Hz, 1H), 4.47-4.21 (m, 2H), 3.67 (s, 2H), 3.05-2.76 (m, 3H), 2.68-2.55 (m, 2H), 2.43-2.32 (m, 4H), 2.18 (br t, J= 10.4 Hz, 2H), 2.03-1.92 (m, 1H), 1.86-1.59 (m, 7H); MS (ESI) m/z: 766.3 [M+H]+.
Scheme 1
Figure imgf000183_0002
Example 2
Preparation of (R)-3 -(6-( 1 -(3 -(4-(( (R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-5-fluoro-1 -methyl- 1H-indazol-3-yl)- 3-methylpiperidine-2, 6-dione A051
Figure imgf000184_0001
[00388] Compound A051 was prepared as shown in Schemes 2A and 2B. 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.08 (s, 1H), 8.90 (d, J= 7.2 Hz, 1H), 8.19 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.73 (t, J= 7.2 Hz, 1H), 7.61 (d, J = 6.0 Hz, 1H), 7.57-7.48 (m, 3H), 7.44 (d, J= 7.6 Hz, 1H), 7.39-7.10 (m, 2H), 5.89-5.77 (m, 1H), 3.98 (s, 3H), 3.64 (s, 2H), 3.02 (d, J= 11.2 Hz, 2H), 2.94-2.82 (m, 1H), 2.61-2.54 (m, 2H), 2.45-2.30 (m, 5H), 2.20-2.04 (m, 3H), 1.91-1.76 (m, 4H), 1.67 (d, J= 7.2 Hz, 3H), 1.61 (s, 3H); MS (ESI) m/z: 779.3 [M+H]+.
Scheme 2 A
Figure imgf000184_0002
Scheme 2B
Figure imgf000185_0001
Preparation of (R)- 1 -(6-( 1 -(3 -(4-(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-5-fluoro-l -methyl- 1H-indazol-3-yl)dihydro- pyrimidine-2,4(1H,3H)-dione A064
Figure imgf000186_0001
[00389] Compound A064 was prepared as shown in Scheme 3. 1H NMR (400 MHz, DMSO-d6 δ 10.5 (s, 1H), 9.08 (s, 1H), 8.90 (d, J= 6.8 Hz, 1H), 8.85 (s, 1H), 8.19 (s, 1H), 8.10 (d, J= 7.2 Hz, 1H), 7.72 (t, J= 7.2 Hz, 1H), 7.60 (d, J= 6.0 Hz, 1H), 7.48-7.55 (m, 2H), 7.44 (d, J= 7.2 Hz, 1H), 7.08-7.39 (m, 3H), 5.82 (t, J= 7.2 Hz, 1H), 3.98 (s, 3H), 3.90 (t, J= 6.4 Hz, 2H), 3.63-3.69 (m, 2H), 3.02 (d, J= 10.2 Hz, 2H), 2.88-2.94 (s, 1H), 2.71-2.78 (m, 2H), 2.42 (s, 3H), 2.15 (t, J = 9.8 Hz, 2H), 1.73-1.93 (m, 4H), 1.67 (d, J = 7.2 Hz, 3 H); MS (ESI) m/z: 766.3 [M+H] 1 .
Scheme 3
Figure imgf000186_0002
Example 4
Preparation of 3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)p5 iperidine-2,6- dione A 102
Figure imgf000187_0001
[00390] Compound A102 was prepared as shown in Scheme 4. 1H NMR (400 MHz, DMSO-d6) δ 10 .79 (s, 1H), 9.08 (s, 1H), 8.96-8.78 (m, 2H), 8.27 (br d, J= 5.2 Hz, 1H), 8.19- 8.10 (m, 1H), 7.72 (br t, J= 7.2 Hz, 1H), 7.52 (br t, J= 6.4 Hz, 1H), 7.45-7.35 (m, 1H), 7.30 (br t, .7= 7.6 Hz, 1H), 7.26-6.93 (m, 4H), 5.87-5.77 (m, 1H), 3.74 (br dd, J= 5.2, 11.2 Hz, 1H), 3.67 (s, 2H), 3.01 (br d, J= 9.6 Hz, 2H), 2.72-2.61 (m, 2H), 2.42 (s, 4H), 2.27 (s, 3H), 2.23-2.09 (m, 3H), 2.06-1.95 (m, 1H), 1.67 (br d, J= 6.4 Hz, 7H); MS (ESI) m/z: 725.2 [M+H]+.
Scheme 4
Figure imgf000187_0002
Example 5
Preparation of 3 -(5 -(4-(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione
B001
Figure imgf000188_0001
[00391] Compound B001 was prepared as shown in Scheme 5. 1H NMR (400 MHz, DMSO-d6) δ 10 .94 (s, 1H), 9.50 (s, 1H), 8.93 (s, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 8.02 (d, J= 6.8 Hz, 1H), 7.65 (s, 1H), 7.62-7.58 (m, 1H), 7.53 (d, J= 2.4 Hz, 1H), 7.51 (d, J= 4.2 Hz, 1H), 7.48 (t, J= 7.2 Hz, 1H), 7.25 (d, J= 5.6 Hz, 1H), 7.09-7.02 (m, 2H), 5.73 (t, J= 6.8 Hz, 1H), 5.04 (dd, J= 5.2, 13.2 Hz, 1H), 4.36-4.28 (m, 1H), 4.24-4.16 (m, 1H), 3.69 (s, 2H), 3.32-3.30 (m, 4H), 2.95-2.83 (m, 1H), 2.74 (s, 3H), 2.71-2.52 (m, 6H), 2.42-2.29 (m, 2H), 2.01-1.90 (m, 1H), 1.66 (d, J= 7.2 Hz, 3H); MS (ESI) m/z: 749.2 [M+H]+.
Figure imgf000188_0002
Example 6 Preparation of 3-(l-methyl-6-(4-(3-(4-methyl-1-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperazin-l-yl)-1H-indazol-3-yl)piperidine-2,6- dione B051
Figure imgf000189_0001
[00392] Compound B051 was prepared as shown in Scheme 6. 1H NMR (400 MHz, DMSO-d6) δ 10 .9 (s, 1H), 9.49 (s, 1H), 8.92 (s, 1H), 8.30 (s, 1H), 8.23 (d, J= 8.0 Hz, 1H), 8.16 (s, 1H), 8.06 (d, J= 6.8 Hz, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.64-7.57 (m, 1H), 7.54 (d, J= 8.0 Hz, 2H), 7.39 (d, J= 7.6 Hz, 1H), 7.33 (dd, J= 8.0 Hz, 1H), 7.09-6.98 (m, 2H), 5.71 (dd, J= 6.8, 6.8 Hz, 1H), 4.34 (dd, J= 5.2, 9.6 Hz, 1H), 4.26 (s, 3H), 3.73 (s, 2H), 3.22-3.06 (m, 2H), 2.92 (d, J = 13.2 Hz, 4H), 2.74 (s, 3H), 2.69-2.61 (m, 2H), 2.59 (s, 3H), 2.57-2.52 (m, 1H), 2.41-2.25 (m, 2H), 2.21-2.12 (m, 1H), 1.62 (d, ./ - 6.8 Hz, 3H).
Figure imgf000189_0002
Example 7
Preparation of (R)- 1 -(6-( 1 -(5 -( 1 -(( 1 -(3 -(difluoromethy l)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorophenethyl)piperidin-4-yl)-l -methyl- 177-indazol-3-yl)- dihydropyrimidine-2, 4(1/7, 3H)-dione B092
Figure imgf000190_0001
[00393] Compound B092 was prepared as shown in Schemes 7A and 7B. 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.61 (s, 1H), 9.07 (s, 1H), 8.42 (dd, ,7 = 7.4, 2.4 Hz, 1H), 8.36- 8.29 (m, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.64 (d, .7 - 8.5 Hz, 1H), 7.57 (t, J= 9.2 Hz, 1H), 7.52 (t, J = 1A Hz, 1H), 7.44 (s, 1H), 7.31-7.24 (m, 2H), 7.07 (dd, J= 8.7, 1.3 Hz, 1H), 5.69-5.63 (m, 1H), 4.00 (s, 3H), 3.92 (t, J= 6.7 Hz, 2H), 3.80 (d, J= 11.7 Hz, 2H), 3.48 (d, J= 9.5 Hz, 4H), 3.30- 3.20 (m, 3H), 3.03 (t, J= 12.2 Hz, 1H), 2.83 (s, 3H), 2.76 (t, J= 6.6 Hz, 2H), 2.17 (d, J= 14.1 Hz, 2H), 2.01 (q, J= 13.4 Hz, 2H), 1.70 (d, .7= 7.0 Hz, 3H); MS (ESI) m/z: 780.3 [M+H] 1.
Scheme 7A
Figure imgf000190_0002
Scheme 7B
Figure imgf000191_0001
Example 8
Preparation of 3-(4-(1-(((R)-4-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B101
Figure imgf000191_0002
[00394] Compound B101 was prepared as shown in Scheme 8. 1H NMR (400 MHz, DMSO-d6) δ 10 .8 (s, 1H), 9.02 (s, 1H), 7.45-7.34 (m, 2H), 7.27-7.18 (m, 2H), 7.14 (d, .7 = 8.4 Hz, 2H), 6.82 (s, 2H), 6.66 (s, 1H), 5.49 (s, 2H), 5.33 (dd, J= 6.8, 6.8 Hz, 1H), 4.51 (d, 12.0
Hz, 1H), 4.25 (d, J= 12.0 Hz, 1H), 4.09-3.99 (m, 1H), 3.81 (dd, J= 4.8, 11.2 Hz, 1H), 3.76-3.60 (m, 2H), 3.13-2.98 (m, 3H), 2.76 (dd, J= 10.8, 13.2 Hz, 1H), 2.70-2.59 (m, 2H), 2.58 (s, 3H), 2.49-2.43 (m, 3H), 2.21-2.11 (m, 2H), 2.10-1.98 (m, 2H), 1.79-1.63 (m, 4H), 1.54 (d, J= 7.2 Hz, 3H); MS (ESI) m/z: 717.5 [M+H] 1 . Scheme 8
Figure imgf000192_0001
Example 9
Preparation of (R)- 1 -(4-( 1 -(5 -( 1 -(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)dihydropyrimidine- 2,4(1 H, 3H)-dione B201
Figure imgf000193_0001
[00396] The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein.
[00397] 3-(5-(1-(3 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione A002. 1H NMR (400 MHz, DMSO-d6) δ 1.67 (d, J= 7.2 Hz, 3H), 1.71-1.86 (m, 4H), 1.93-2.04 (m, 1H), 2.09-2.24 (m, 2H), 2.31-2.40 (m, 1H), 2.42 (s, 3H), 2.55-2.62 (m, 1H), 2.64-2.74 (m, 1H), 2.84-2.95 (m, 1H), 2.96-3.09 (m, 2H), 3.59-3.74 (m, 2H), 4.22-4.33 (m, 1H), 4.36-4.48 (m, 1H), 5.09 (dd, 13.2, 4.8 Hz, 1H), 5.83 (t, J= 7.2 Hz, 1H), 7.09-7.27 (m, 1H), 7.27-7.34 (m, 1H), 7.37-7.47 (m, 2H), 7.48-7.57 (m, 3H), 7.64 (d, .7= 7.6 Hz, 1H), 7.73 (t, ./= 7.2 Hz, 1H), 8.11 (d, J= 7.6 Hz, 1H), 8.15 (s, 1H), 8.17-8.23 (m, 1H), 8.86 (s, 1H), 8.92 (d, J= 7.2 Hz, 1H), 9.08 (s, 1H), 10.97 (s, 1H); MS (ESI) m z. 748.3 [M+H]+.
Figure imgf000194_0001
[00398] 3-(5-(1-(3-(4-(((R)-1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A003. 1H NMR (400 MHz, DMSO-d6) δ 10 .97 (s, 1H), 9.05 (s, 1H), 8.92 (br d, J= 6.8 Hz, 1H), 8.82 (s, 1H), 8.28 (dd, J= 2.4, 7.2 Hz, 1H), 8.15 (s, 1H), 8.13 (dt, J= 2.8, 5.6 Hz, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.63 (d, J= 6.4 Hz, 1H), 7.45 (d, J= 9.2 Hz, 1H), 7.42-7.35 (m, 2H), 7.22 (s, 2H), 5.88-5.72 (m, 1H), 5.14-5.02 (m, 1H), 4.43-4.34 (m, 1H), 4.30-4.20 (m, 1H), 3.68 (s, 2H), 3.03 (d, J= 10.4 Hz, 2H), 2.97-2.85 (m, 2H), 2.60 (d, J= 2.4 Hz, 1H), 2.56 (s, 3H), 2.43 (s, 3H), 2.40-2.31 (m, 1H), 2.26-2.14 (m, 2H), 2.03-1.94 (m, 1H), 1.83-1.71 (m, 4H), 1.61 (d, J= 6.8 Hz, 3H).
Figure imgf000194_0002
[00399] 3 -(5 -( 1 -(5 -(4-(((R)- 1 -(3 -(Difluoromethy l)-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l -oxoisoindolin-2-yl)- piperidine-2, 6-dione A004. 1H NMR (400 MHz, DMSO-d6) δ 10 .96 (s, 1H), 9.06-9.04 (m, 1H), 8.93 (d, .7= 6.8 Hz, 1H), 8.83 (s, 1H), 8.33-8.26 (m, 1H), 8.17 (s, 1H), 8.16-8.10 (m, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.63 (d, J= 7.6 Hz, 1H), 7.50 (s, 1H), 7.43-7.35 (m, 3H), 7.31 (d, J= 7.6 Hz, 1H), 7.29-7.07 (m, 1H), 5.83-5.74 (m, 1H), 5.13-5.05 (m, 1H), 4.46-4.36 (m, 1H), 4.33-4.24 (m, 1H), 3.67 (s, 2H), 3.02 (d, J= 11.2 Hz, 2H), 2.96-2.85 (m, 1H), 2.61 (s, 2H), 2.56 (s, 4H), 2.44- 2.41 (m, 3H), 2.40-2.31 (m, 1H), 2.25-2.10 (m, 2H), 2.01-1.93 (m, 1H), 1.83-1.69 (m, 3H), 1.61 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 762.1 [M+H]+.
Figure imgf000195_0001
[00400] 3-(5-(1-((5-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4--d]pyrimidin-6-yl)pyri din-3 -yl)methyl)piperidin-4-yl)-6-fluoro- 1-oxo- isoindolin-2-yl)piperidine-2, 6-dione A005. 1H NMR (400 MHz, DMSO-d6) δ 10 .98 (s, 1H), 9.34-9.30 (m, 1H), 9.12 (s, 1H), 8.98 (s, 1H), 8.90 (d, J= 6.8 Hz, 1H), 8.62-8.59 (m, 1H), 8.48 (s, 1H), 7.73 (t, J= 7.2 Hz, 1H), 7.65 (d, J= 6.0 Hz, 1H), 7.55-7.50 (m, 1H), 7.46 (d, J= 9.2 Hz, 1H), 7.31 (t, J= 7.6 Hz, 1H), 7.25-7.10 (m, 1H), 5.82 (t, .7 = 7.6 Hz, 1H), 5.10 (dd, J= 4.8, 12.8 Hz, 1H), 4.44-4.24 (m, 2H), 3.68 (s, 2H), 3.00 (d, J= 9.2 Hz, 2H), 2.96-2.85 (m, 2H), 2.74-2.55 (m, 2H), 2.43 (s, 4H), 2.22-2.14 (m, 2H), 2.02-1.96 (m, 1H), 1.78 (s, 3H), 1.68 (d, J= 7.2 Hz, 3H); MS (ESI) m/z: 1612 [M+H]+.
Figure imgf000195_0002
[00401] (R)- 1 -(6-( 1 -(5 -( 1 -(( 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-1H-indazol-3-yl)dihydro- pyrimidine-2, 4(1H,3H)-dione A061. 1H NMR (400 MHz, DMSO-d6) δ 10 .53 (s, 1H), 9.08 (d, J = 0.8 Hz, 1H), 8.90 (d, J= 7.1 Hz, 1H), 8.84 (d, J= 1.0 Hz, 1H), 8.29 (dd, J = 12, 2.4 Hz, 1H), 8.14 (ddd, J= 7.8, 4.9, 2.5 Hz, 1H), 7.72 (t, J= 1A Hz, 1H), 7.52 (dd, J= 13.3, 7.8 Hz, 2H), 7.45 (s, 1H), 7.42-7.38 (m, 1H), 7.30 (t, J= 7.7 Hz, 1H), 7.04 (dd, J= 8.6, 1.3 Hz, 1H), 5.82 (p, J = 7.0 Hz, 1H), 4.55 (s, 1H), 3.95 (s, 3H), 3.89 (t, J= 6.6 Hz, 2H), 3.67 (s, 2H), 3.03 (d, J= 10.9 Hz, 2H), 2.74 (t, J= 6.7 Hz, 2H), 2.70-2.62 (m, 1H), 2.42 (s, 3H), 2.23-2.15 (m, 2H), 1.80 (s, 4H), 1.67 (d, J= 7.0 Hz, 3H); MS (ESI) m/z: 766.3 [M+H]+.
Figure imgf000196_0001
[00402] (R)- 1 -(6-( 1 -(5 -(4-(( 1 -(3 -(Difluoromethy l)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorophenethyl)piperidin-4-yl)-l-m ethyl- 1H-indazol-3-yl)- dihydropyrimidine-2, 4(1H,3H)-dione A062. MS (ESI) m/z: 780.3 [M+H]+.
Figure imgf000196_0002
[00403 ] (R)- 1 -(6-( 1 -(5 -(4-(( 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-5-fluoro-l -methyl- 1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione A063. 1H NMR (400 MHz, DMSO-d6) δ 10 .54 (s, 1H), 9.08 (s, 1H), 8.89 (d, J= 7.2 Hz, 1H), 8.84 (s, 1H), 8.30 (dd, J= 2.0, 7.2 Hz, 1H), 8.15 (s, 1H), 8.13 (dd, J= 2.8, 5.6 Hz, 1H), 7.60 (d, J= 6.0 Hz, 1H), 7.54-7.48 (m, 1H), 7.43-7.38 (m, 1H), 7.36 (d, J= 10.8 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.26-7.08 (m, 1H), 5.82 (t, J= 12 Hz, 1H), 3.97 (s, 3H), 3.89 (t, J= 6.8 Hz, 2H), 3.68 (s, 2H), 3.05 (d, J= 11.2 Hz, 2H), 2.88 (dd, J= 52, 10.0 Hz, 1H), 2.74 (t, J = 6.8 Hz, 2H), 2.42 (s, 3H), 2.28-2.16 (m, 2H), 1.91-1.75 (m, 4H), 1.67 (d, J= 12 Hz, 3H); MS (ESI) m/z: 784.2 [M+H]+.
Figure imgf000197_0001
[00404] (R)-3-(4-(1-(5-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-
2,6-dione A101. 1H NMR (400 MHz, DMSO-d6) δ 10 .88 (s, 1H), 9.07 (d, J= 0.7 Hz, 1H), 8.90 (d, J= 7.2 Hz, 1H), 8.83 (s, 1H), 8.29-8.24 (m, 1H), 8.14 (ddd, J= 7.9, 5.1, 2.5 Hz, 1H), 7.72 (t, J= 7.4 Hz, 1H), 7.52 (t, J = 7.0 Hz, 1H), 7.39 (t, J = 9.1 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.26 (d, J= 1.9 Hz, 1H), 7.24 (s, 2H), 7.19 (d, J= 1.9 Hz, 1H), 7.18 (d, J= 1.9 Hz, 1H), 5.82 (p, J= 7.1 Hz, 1H), 4.56 (s, 1H), 3.65 (s, 2H), 2.99 (d, J= 10.8 Hz, 2H), 2.44 (d, J= 3.7 Hz, 1H), 2.41 (s, 3H), 2.36-2.30 (m, 1H), 2.14 (s, 1H), 2.11-1.97 (m, 2H), 1.91 (s, 2H), 1.75 (d, J= 12.6 Hz, 2H), 1.67 (d, J= 7.1 Hz, 4H), 1.40 (s, 3H); MS (ESI) m/z: 1253 [M+H]+.
Figure imgf000197_0002
[00405] (R)-3-(4-(l -(5-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3 -methyl - piperidine-2, 6-dione A103. 1H NMR (400 MHz, DMSO-d6) δ 10 .85 (s, 1H), 9.07 (s, 1H), 8.90 (br d, J= 7.2 Hz, 1H), 8.83 (s, 1H), 8.27 (br d, J= 6.0 Hz, 1H), 8.16 (s, 1H), 8.14 (br s, 1H), 7.72 (br t, J= 7.2 Hz, 1H), 7.52 (br t, J= 7.6 Hz, 1H), 7.43-7.36 (m, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.26-6.96 (m, 4H), 5.82 (br t, J= 7.2 Hz, 1H), 3.67 (s, 2H), 3.00 (br d, J= 10.4 Hz, 2H), 2.69- 2.63 (m, 1H), 2.41 (s, 4H), 2.35-2.30 (m, 1H), 2.28 (s, 3H), 2.23-2.12 (m, 2H), 2.10-1.97 (m, 2H), 1.71-1.60 (m, 7H), 1.39 (s, 3H); MS (ESI) m/z: 739.2 [M+H]+.
Figure imgf000198_0001
[00406] (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-7]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2,6-dione A104. 1H NMR (400 MHz, DMSO-d6) δ 10 .86 (s, 1H), 9.08 (s, 1H), 8.91 (d, 7= 7.2 Hz, 1H), 8.85 (s, 1H), 8.17 (s, 1H), 8.10 (d, 7= 8.0 Hz, 1H), 7.72 (br t, 7= 7.2 Hz, 1H), 7.55- 7.49 (m, 2H), 7.42 (d, 7= 7.6 Hz, 1H), 7.39-7.30 (m, 1H), 7.29-7.11 (m, 2H), 7.06-7.01 (m, 2H), 5.82 (quin, 7= 7.2 Hz, 1H), 3.62 (s, 2H), 2.98 (br d, 7= 10.8 Hz, 2H), 2.72-2.62 (m, 1H), 2.42 (s, 4H), 2.36-2.31 (m, 1H), 2.28 (s, 3H), 2.15-2.01 (m, 4H), 1.67 (br d, 7= 7.2 Hz, 7H), 1.39 (s, 3H); MS (ESI) m z\ 721.2 [M+H]+.
Figure imgf000198_0002
[00407] (R)-3-(4-(1-(5-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-7]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)- 3-methylpiperidine-2, 6-dione A105. 1H NMR (400 MHz, DMSO-d6) δ 10 .98 (s, 1H), 9.08 (s, 1H), 8.90 (d, 7= 7.2 Hz, 1H), 8.84 (s, 1H), 8.28 (dd, 7= 2.4, 7.2 Hz, 1H), 8.15 (ddd, 7= 2.4, 5.4, 8.0 Hz, 1H), 7.78-7.66 (m, 2H), 7.59-7.48 (m, 3H), 7.44-7.10 (m, 3H), 5.83 (quin, 7= 7.2 Hz, 1H), 3.68 (s, 2H), 3.04 (br d, 7= 10.4 Hz, 2H), 2.86-2.73 (m, 1H), 2.48-2.37 (m, 5H), 2.20-2.03 (m, 4H), 1.81 (q, 7= 11.2 Hz, 2H), 1.68 (br d, 7= 7.2 Hz, 5H), 1.47 (s, 3H); MS (ESI) m/z. 793.3 [M+H]+.
Figure imgf000199_0001
[00408] (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fIuorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione A106. 1H NMR (400 MHz, DMSO-d6) δ 10 .98 (s, 1H), 9.08 (s, 1H), 8.91 (br d, J= 7.2 Hz, 1H), 8.85 (s, 1H), 8.17 (s, 1H), 8.10 (br d, J= 7.6 Hz, 1H), 7.77-7.64 (m, 2H), 7.60-7.48 (m, 4H), 7.43 (br d, J= 7.6 Hz, 1H), 7.40-7.08 (m, 2H), 5.83 (quin, J= 6.8 Hz, 1H), 3.62 (s, 2H), 3.00 (br d, J= 10.4 Hz, 2H), 2.80 (br t, J= 11.2 Hz, 1H), 2.53 (br s, 1H), 2.42 (s, 4H), 2.16-2.02 (m, 4H), 1.88-1.73 (m, 2H), 1.67 (br d, J= 6.8 Hz, 5H), 1.47 (s, 3H); MS (ESI) m/z: 1152 [M+H]+.
Figure imgf000199_0002
[00409] (R)-3-(4-(1-(3-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3 -methyl - piperidine-2, 6-dione A107. 1H NMR (400 MHz, DMSO-d6) δ 10 .88 (s, 1H), 9.08 (s, 1H), 8.91 (d, .7= 7.2 Hz, 1H), 8.85 (s, 1H), 8.16 (s, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.73 (br t, J= 7.6 Hz, 1H), 7.55-7.48 (m, 2H), 7.42 (d, J= 7.6 Hz, 1H), 7.38-7.10 (m, 2H), 6.93-6.84 (m, 2H), 5.83 (quin, ,7= 7.2 Hz, 1H), 3.61 (s, 2H), 2.97 (br d, .7= 8.0 Hz, 2H), 2.82-2.71 (m, 1H), 2.45 (br d, J = 13.6 Hz, 1H), 2.42 (s, 3H), 2.39-2.34 (m, 1H), 2.32 (s, 3H), 2.13-1.99 (m, 6H), 1.67 (d, J= 12 Hz, 3H), 1.63-1.55 (m, 2H), 1.40 (s, 3H); MS (ESI) m/z: 739.3 [M+H]+.
Figure imgf000200_0001
[00410] (R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione A108. 1H NMR (400 MHz, DMSO-d6) δ 10 .92-10.84 (m, 1H), 9.07 (s, 1H), 8.90 (br d, J = 7.2 Hz, 1H), 8.83 (s, 1H), 8.31-8.21 (m, 1H), 8.14 (td, J= 2.8, 5.6 Hz, 1H), 7.72 (br t, J= 7.2 Hz, 1H), 7.52 (br t, J= 6.8 Hz, 1H), 7.41-7.11 (m, 3H), 6.96-6.85 (m, 2H), 5.82 (quin, J= 6.8 Hz, 1H), 3.65 (s, 2H), 2.98 (br d, J= 10.4 Hz, 2H), 2.78-2.70 (m, 1H), 2.46-2.39 (m, 4H), 2.35 (br dd, J= 3.6, 9.6 Hz, 1H), 2.31 (s, 3H), 2.16-1.97 (m, 6H), 1.67 (d, J = 7.2 Hz, 3H), 1.60 (br d, J= 10.8 Hz, 2H), 1.42-1.36 (m, 3H); MS (ESI) 1512 [Mm+H/z]:+.
Figure imgf000200_0002
[00411 ] (R)-3 -(3 -Cyclopropyl-4-(l -(5-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A109. 1H NMR (400 MHz, DMSO-d6) δ 10 .85 (s, 1H), 9.07 (s, 1H), 8.89 (d, .7= 6.8 Hz, 1H), 8.83 (s, 1H), 8.30-8.22 (m, 1H), 8.14 (d, J= 3.2 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.52 (t, J= 6.8 Hz, 1H), 7.42-7.35 (m, 1H), 7.30 (t, J= 7.6 Hz, 1H), 7.23 (d, J= 6.4 Hz, 2H), 7.13-7.00 (m, 1H), 6.84 (s, 1H), 5.82 (t, .7 = 7.2 Hz, 1H), 3.67 (s, 2H), 3.14-2.95 (m, 3H), 2.41 (s, 4H), 2.35-2.28 (m, 1H), 2.18 (t, J= 10.4 Hz, 2H), 2.08-1.92 (m, 3H), 1.77-1.63 (m, 7H), 1.37 (s, 3H), 0.90 (d, J= 8.4 Hz, 2H), 0.55 (d, J= 4.4 Hz, 2H); MS (ESI) m/fr. 1652 [M+H]+.
Figure imgf000201_0001
[00412] (R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-7]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3-methyl- piperidine-2, 6-dione A110. 1 H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H), 1.71 (s, 4H), 2.05 (s, 1H), 2.08 (s, 1H), 2.10-2.22 (m, 3H), 2.31-2.39 (m, 1H), 2.41 (s, 3H), 2.44 (d, 7= 2.8 Hz, 1H), 2.70-2.82 (m, 1H), 2.99 (d, J= 11.2 Hz, 2H), 3.65 (s, 2H), 5.82 (q, J = 6.8 Hz, 1H), 7.01 (dd, J= 8.0, 1.5 Hz, 1H), 7.06-7.13 (m, 1H), 7.27-7.33 (m, 1H), 7.34-7.42 (m, 2H), 7.52 (t, 7= 6.6 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 8.09-8.17 (m, 1H), 8.22-8.30 (m, 1H), 8.83 (s, 1H), 8.89 (d, J= 7.2 Hz, 1H), 9.07 (s, 1H), 10.92 (s, 1H); MS (ESI) m/z: 743.2 [M+H]+.
Figure imgf000201_0002
[00413] (R) - 3 -(3 -Cyclopropyl -4-( 1 -(3-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A1li. 1H NMR (400 MHz, DMSO-d6) δ 10 .86 (s, 1H), 9.08 (s, 1H), 8.91 (d, J= 6.4 Hz, 1H), 8.85 (s, 1H), 8.17 (s, 1H), 8.10 (d, J= 7.6 Hz, 1H), 7.72 (t, J= 7.2 Hz, 1H), 7.56-7.48 (m, 2H), 7.43 (d, 7 = 7.2 Hz, 1H), 7.40-7.09 (m, 3H), 7.04 (d, 7 = 8.4 Hz, 1H), 6.84 (s, 1H), 5.82 (t, J= 7.2 Hz, 1H), 3.63 (s, 2H), 3.16-2.95 (m, 3H), 2.42 (s, 4H), 2.32 (s, 1H), 2.13 (t, 7= 9.2 Hz, 2H), 2.07-1.94 (m, 3H), 1.77-1.61 (m, 7H), 1.38 (s, 3H), 0.90 (d, 7= 8.4 Hz, 2H), 0.55 (d, 7= 5.2 Hz, 2H); MS (ESI) m/z: 747.1 [M+H]+.
Figure imgf000202_0001
[00414] 3 - (4 - ( 1 -(3 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione A112.
’HNMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.09 (s, 1H), 8.92 (br d, J= 7.2 Hz, 1H), 8.86 (s, 1H), 8.18 (s, 1H), 8.11 (br d, J= 8.0 Hz, 1H), 7.78-7.68 (m, 1H), 7.58-7.49 (m, 2H), 7.44 (br d, J = 7.6 Hz, 1H), 7.40-7.09 (m, 3H), 7.03-6.93 (m, 2H), 5.83 (br t, J= 7.2 Hz, 1H), 3.75 (br dd, J = 4.9, 11.1 Hz, 1H), 3.64 (s, 2H), 3.00 (br d, J= 10.4 Hz, 2H), 2.75-2.58 (m, 2H), 2.43 (s, 4H), 2.28 (s, 3H), 2.14 (br d, J= 6.4 Hz, 3H), 2.06-1.96 (m, 1H), 1.68 (br d, J= 6.4 Hz, 7H); MS (ESI) m/z-. 707.3 [M+H]+.
Figure imgf000202_0002
[00415] (R)-3 -(3 -Chloro-4-( 1 -(5-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-2-methylpyrido[3,4--d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A113. 1H NMR (400 MHz, DMSO-d6) 3 1.42 (s, 3H), 1.61-1.69 (m, 4H), 1.69-1.79 (m, 3H), 1.99-2.12 (m, 2H), 2.12-2.23 (m, 2H), 2.38 (d, J= 8.4 Hz, 1H), 2.41 (s, 3H), 2.46 (s, 1H), 2.82-2.95 (m, 1H), 3.02 (d, J= 10.0 Hz, 2H), 3.67 (s, 2H), 5.75-5.89 (m, 1H), 7.09- 7.25 (m, 2H), 7.26-7.33 (m, 2H), 7.35-7.45 (m, 2H), 7.52 (t, J= 6.8 Hz, 1H), 7.72 (t, J= 7.2 Hz, 1H), 8.10-8.18 (m, 1H), 8.23-8.30 (m, 1H), 8.83 (s, 1H), 8.89 (d, J = 6.8 Hz, 1H), 9.07 (s, 1H), 10.93 (s, 1H); MS (ESI) m/z: 759.2 [M+H]+.
Figure imgf000203_0001
[00416] (R)-3 -(3 -Chloro-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethy 1)- amino)-2-methylpyrido[3,4-d]pyrirnidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-rnethylpiperidine- 2,6-dione A114. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 3H), 1.67 (d, J= 6.8 Hz, 4H), 1.70- 1.80 (m, 3H), 2.07 (d, J= 10.4 Hz, 2H), 2.11-2.24 (m, 2H), 2.38 (d, J= 8.8 Hz, 1H), 2.42 (s, 3H), 2.46 (s, 1H), 2.92 (t, J= 10.8 Hz, 1H), 3.02 (d, J= 10.0 Hz, 2H), 3.66 (s, 2H), 5.82 (quin, J = 6.8 Hz, 1H), 7.09-7.26 (m, 2H), 7.27-7.34 (m, 2H), 7.36-7.46 (m, 2H), 7.49-7.57 (m, 2H), 7.73 (t, J= 7.2 Hz, 1H), 8.08-8.15 (m, 1H), 8.18 (s, 1H), 8.86 (s, 1H), 8.88-8.95 (m, 1H), 9.08 (s, 1H), 10.94 (s, 1H); MS (ESI) m z. 741.2 [M+H]+.
Figure imgf000203_0002
[00417] (R)-3-(4-(1-((5-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-l-methyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)piperidin- 4-yl)phenyl)-3-methylpiperidine-2, 6-dione A115. 1H NMR (400 MHz, DMSO-d6) d 10.88 (s, 1H), 9.03 (s, 1H), 8.77 (d, J= 7.2 Hz, 1H), 8.61 (s, 1H), 8.54 (s, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 7.80-7.67 (m, 1H), 7.57-7.47 (m, 1H), 7.40-7.08 (m, 6H), 5.82 (t, J= 7.2 Hz, 1H), 3.85 (d, J = 1.6 Hz, 2H), 3.66 (s, 3H), 3.26 (s, 3H), 2.76-2.58 (m, 2H), 2.46 (s, 1H), 2.41 (s, 3H), 2.37-2.30 (m, 1H), 2.14-1.99 (m, 2H), 1.93-1.77 (m, 4H), 1.67 (d, ./ - 7.2 Hz, 3H), 1.41 (s, 3H); MS (ESI) m/z: 738.3 [M+H]+.
Figure imgf000204_0001
[00418] (R)-3 -(3 -(Difluoromethyl)-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethy l)-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A116. 1H NMR (400 MHz, DMSO-d6) δ 10 .95 (s, 1H), 9.08 (s, 1H), 8.91 (br d, 7.2 Hz, 1H), 8.85 (s, 1H), 8.17 (s, 1H), 8.10 (br d, J= 7.6 Hz, 1H), 7.72 (br t, J = 7.2 Hz, 1H), 7.52 (br dd, J= 4.8, 7.6 Hz, 3H), 7.45-7.39 (m, 3H), 7.38-7.10 (m, 3H), 5.87-5.78 (m, 1H), 3.62 (br s, 2H), 2.98 (br d, J= 10.4 Hz, 2H), 2.89-2.83 (m, 1H), 2.48-2.45 (m, 1H), 2.42 (s, 3H), 2.37 (br dd, J= 4.4, 8.8 Hz, 1H), 2.16-2.02 (m, 4H), 1.81-1.71 (m, 2H), 1.67 (br d, J = 7.2 Hz, 5H), 1.44 (s, 3H); MS (ESI) m/z: 1512 [M+H]+.
Figure imgf000204_0002
[00419] (R)-3 -(3 -(Difluoromethyl)-4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3-methylpiperidine-2, 6-dione A117. 1H NMR (400 MHz, DMSO-d6) δ 10 .94 (s, 1H), 9.07 (s, 1H), 8.89 (d, J= 6.8 Hz, 1H), 8.83 (s, 1H), 8.29-8.23 (m, 1H), 8.18-8.11 (m, 1H), 7.72 (t, J= 7.2 Hz, 1H), 7.55-7.48 (m, 2H), 7.45-7.31 (m, 4H), 7.30-7.10 (m, 2H), 5.82 (quin, J= 12 Hz, 1H), 3.67 (s, 2H), 2.99 (br d, J= 12 Hz, 2H), 2.90-2.80 (m, 1H), 2.48-2.43 (m, 1H), 2.41 (s, 3H), 2.40-2.32 (m, 1H), 2.16 (br t, 11.2 Hz, 2H), 2.11-2.00 (m, 2H), 1.80-1.71 (m, 2H), 1.69- 1.63 (m, 5H), 1.43 (s, 3H); MS (ESI) m/z: 775.2 [M+H]+.
Figure imgf000205_0001
[00420] (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione A118. 1H NMR (400 MHz, DMSO-d6) δ 10 .95 (s, 1H), 9.08 (s, 1H), 8.91 (d, J= 7.2 Hz, 1H), 8.85 (s, 1H), 8.16 (s, 1H), 8.10 (d, J= 7.6 Hz, 1H), 7.73 (t, J= 12 Hz, 1H), 7.58-7.49 (m, 2H), 7.46-7.08 (m, 3H), 6.98 (d, J= 10.4 Hz, 2H), 5.82 (quin, J= 7.2 Hz, 1H), 3.61 (s, 2H), 2.97 (d, J= 9.2 Hz, 2H), 2.93-2.85 (m, 1H), 2.46 (d, J = 4.4 Hz, 1H), 2.42 (s, 3H), 2.40-2.31 (m, 1H), 2.22-2.11 (m, 1H), 2.10-1.92 (m, 5H), 1.67 (d, J= 6.8 Hz, 5H), 1.44 (s, 3H); MS (ESI) m/z: 743.3 [M+H]+.
Figure imgf000205_0002
[00421] 3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluoropheny l)ethyl)amino)-2-methy 1- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- dione A119. 1H NMR (400 MHz, DMSO-d6) δ 10 .82 (s, 1H), 9.08 (s, 1H), 8.93 (d, J= 7.1 Hz, 1H), 8.86 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.57-7.49 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.39-7.10 (m, 2H), 6.88-6.80 (m, 2H), 5.83 (quin, J = 6.8 Hz, 1H), 3.77 (dd, J= 4.8, 12.0 Hz, 1H), 3.65 (s, 2H), 3.00 (d, J= 9.2 Hz, 2H), 2.83-2.74 (m, 1H), 2.68-2.59 (m, 1H), 2.47 (s, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 2.25-2.16 (m, 1H), 2.10 (t, J = 10.8 Hz, 3H), 2.05-1.94 (m, 2H), 1.67 (d, J= 7.2 Hz, 3H), 1.64-1.56 (m, 2H); MS (ESI) m/z: 1252 [M+H]+.
Figure imgf000206_0001
[00422] 3-(4-(1-(5-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)- piperidine-2, 6-dione A120. 1H NMR (400 MHz, DMSO-d6) δ 10 .81 (s, 1H), 9.08 (s, 1H), 8.90 (d, J= 7.2 Hz, 1H), 8.84 (s, 1H), 8.27 (dd, J= 2.0, 7.2 Hz, lH), 8.16 (s, 1H), 8.15-8.11 (m, 1H), 7.72 (t, J= 7.6 Hz, 1H), 7.52 (t, J= 6.8 Hz, 1H), 7.43-7.36 (m, 1H), 7.31 (t, J= 7.8 Hz, 1H), 7.11 (s, 1H), 6.92-6.78 (m, 2H), 5.86-5.78 (m, 1H), 3.77 (dd, J= 4.8, 11.6 Hz, 1H), 3.67 (s, 2H), 2.99 ( d, J= 10.4 Hz, 2H), 2.81-2.71 (m, 1H), 2.63 (dt, J= 5.6, 11.6 Hz, 1H), 2.41 (s, 3H), 2.31 (s, 3H), 2.22-2.10 (m, 3H), 2.09-1.96 (m, 3H), 1.67 (d, J= 7.2 Hz, 3H), 1.61 (d, J= 10.8 Hz, 2H); MS (ESI) m/z: 743.3 [M+H]+.
Figure imgf000206_0002
[00423 ] (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2,3-difluorophenyl)-3-methyl- piperidine-2, 6-dione A121. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J= 5.2 Hz, 1H), 8.95 (s, 1H), 8.14-7.88 (m, 3H), 7.62-7.31 (m, 4H), 7.22-7.12 (m, 1H), 7.05-6.72 (m, 3H), 6.46 (s, 1H), 5.89-5.75 (m, 1H), 3.80-3.61 (m, 2H), 3.17 (s, 2H), 2.90 (d, J= 3.2 Hz, 1H), 2.61 (d, J= 5.2 Hz, 3H), 2.59-2.47 (m, 2H), 2.37 (dd, J = 7.6, 13.2 Hz, 1H), 2.19 (d, J= 7.2 Hz, 2H), 1.94-1.81 (m, 4H), 1.69 (s, 3H), 1.63 (d, J= 4.8 Hz, 3H).
Figure imgf000207_0001
[00424] (R)-3-(4-(1-(5-(4-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methyl-piperidine-2, 6-dione A122. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.07 (s, 1H), 8.89 (d, J= 7.2 Hz, 1H), 8.83 (s, 1H), 8.26 (dd, J= 2.0, 7.2 Hz, 1H), 8.19-8.06 (m, 1H), 7.72 (t, J= 7.2 Hz, 1H), 7.57-7.48 (m, 1H), 7.39 (s, 1H), 7.27 (d, J= 23.6 Hz, 2H), 6.97 (d, J = 10.4 Hz, 2H), 5.87-5.75 (m, 1H), 3.65 (s, 2H), 2.97 (s, 2H), 2.93-2.82 (m, 1H), 2.47 (bd, J= 52 Hz, 1H), 2.41 (s, 3H), 2.40-2.34 (m, 1H), 2.19-1.91 (m, 6H), 1.67 (d, J= 12 Hz, 5H), 1.43 (s, 3H); MS (ESI) m2'. 761.4 [M+H]+.
Figure imgf000207_0002
[00425 ] (R)-3 -(4-( 1 -(( (R)- 1 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-
2-methylpyrido[3,4-d]pyrimidin-6-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione A123. 1H NMR. (400 MHz, DMSO-d6) δ 10 .84 (s, 1H), 8.64 (s, 1H), 8.41 (d, J= 7.8 Hz, 2H), 7.60 (t, J= 12 Hz, 1H), 7.44-7.47 (m, 2H), 7.19-7.27 (m, 3H), 7.02-7.08 (m, 2H), 5.74 (t, J= 12 Hz, 1H), 4.05-4.09 (m, 1H), 3.57-3.72 (m, 1H), 3.43-3.54 (m, 2H), 2.96 (t, J= 12 Hz, 2H), 2.28-2.32 (m, 3H), 2.30-2.32 (m, 3H), 2.28-2.30 (m, 2H), 1.72- 2.02 (m, 6H), 1.60-1.69 (m, 3H), 1.60 (s, 3H), 1.38 (s, 3H).
Figure imgf000208_0001
[00426] (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2-fluoro-3-methylphenyl)-3-methyl- piperidine-2, 6-dione A124. 1H NMR (400 MHz, DMSO-d6) δ 10 .83 (s, 1H), 9.08 (s, 1H), 8.91 (d, J= 6.8 Hz, 1H), 8.85 (s, 1H), 8.17 (d, J= 5.6 Hz, 1H), 8.10 (d, J= 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.58-7.47 (m, 2H), 7.45-7.37 (m, 1H), 7.30 (t, J= 7.6 Hz, 1H), 7.17-7.05 (m, 2H), 5.98-5.61 (m, 1H), 3.64 (s, 3H), 3.00 (d, J= 8.8 Hz, 2H), 2.70 (td, J= 5.2, 10.4 Hz, 2H), 2.42 (s, 3H), 2.37-2.21 (m, 3H), 2.16 (s, 5H), 1.81-1.74 (m, 1H), 1.67 (d, J= 6.8 Hz, 6H), 1.56 (s, 3H); MS (ESI) m/z: 739.4 [M+H]+.
Figure imgf000208_0002
[00427] 3-(6-Fluoro-5-(1-(3-(4-methyl-1-(((R)-1-(2-rnethyl-3-(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione B002. 1H NMR (400 MHz, DMSO-d6) <5 11.0 (s, 1H), 9.48 (s, 1H), 8.91 (s, 1H), 8.27 (s, 1H), 8.21 (d, J= 8.0 Hz, 1H), 8.19 (s, 1H), 8.06 (d, J= 6.8 Hz, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.66-7.44 (m, 5H), 7.32 (t, J = 8.0 Hz, 1H), 5.71 (q, J= 6.8 Hz, 1H), 5.10 (dd, J= 5.2, 13.2 Hz, 1H), 4.45-4.35 (m, 1H), 4.33-4.21 (m, 1H), 3.67 (s, 2H), 3.02 (d, J= 10.8 Hz, 2H), 2.97-2.83 (m, 2H), 2.74 (s, 3H), 2.59 (s, 3H), 2.40 (dt, J= 4.4, 13.2 Hz, 2H), 2.16 (s, 2H), 2.04-1.93 (m, 1H), 1.78 (s, 4H), 1.61 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 780.4 [M+H]+.
Figure imgf000209_0001
[00428] 3-(5-(4-(3-(1-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B003. 1H NMR (400 MHz, DMSO-d6) δ 11.0 (s, 1H), 9.47 (s, 1H), 8.89 (s, 1H), 8.29 (s, 1H), 8.26-8.18 (m, 2H), 8.06 (br d, J= 6.4 Hz, 1H), 7.79 (d, J= 7.6 Hz, 1H), 7.68-7.41 (m, 5H), 7.31 (t, J= 7.6 Hz, 1H), 5.60 (quin, J = 6.4 Hz, 1H), 5.17-5.03 (m, 1H), 4.45-4.35 (m, 1H), 4.33-4.23 (m, 1H), 3.78-3.57 (m, 3H), 3.17 (br d, J= 2.0 Hz, 1H), 3.09-2.82 (m, 4H), 2.73 (s, 3H), 2.68 (s, 3H), 2.59 (br d, J= 16.0 Hz, 1H), 2.38 (dq, J= 4.4, 13.2 Hz, 1H), 2.15 (br s, 1H), 2.05-1.92 (m, 1H), 1.78 (br s, 3H), 1.60 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 737.2 [M+H]2
Figure imgf000209_0002
[00429] 3-(5-(1-(5-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-6-fluoro-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B004. MS (ESI) m/z' \ 784.2 [M+H]+.
Figure imgf000209_0003
[00430] 3-(5-(1-(5-(l -(((R)- 1 -(3 -(Difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B005. 1H NMR (400 MHz, DMSO-d6) δ 10 .98 (s, 1H), 9.73 (s, 1H), 9.20 (s, 1H), 8.69 (dd, J= 7.1, 2.4 Hz, 1H), 8.56-8.49 (m, 1H), 7.76-7.64 (m, 3H), 7.44 (d, J= 9.1 Hz, 2H), 7.38 (d, J= 7.9 Hz, 1H), 7.30 (t, J= 7.7 Hz, 1H), 7.24 (s, 1H), 5.59-5.53 (m, 1H), 5.10 (dd, J= 13.3, 5.1 Hz, 1H), 4.59 (s, 2H), 4.44 (d, J= 17.4 Hz, 1H), 4.31 (d, J= 17.4 Hz, 1H), 3.61 (d, J= 11.3 Hz, 3H), 3.38-3.34 (m, 2H), 3.04-2.96 (m, 1H), 2.90 (s, 3H), 2.65-2.55 (m, 1H), 2.54- 2.51 (m, 3H), 2.43-2.31 (m, 1H), 2.08 (d, J= 13.5 Hz, 2H), 2.03-1.89 (m, 4H), 1.65 (d, J= 6.9 Hz, 3H); MS (ESI) m/z: 762.3 [M+H]+.
Figure imgf000210_0001
[00431] 3-(5-(1-(5-(l -(((R)- 1 -(3 -(Difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-6-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione B006. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.75 (s, 1H), 9.22 (s, 1H), 8.69 (dd, J= 7.3, 2.4 Hz, 1H), 8.53 (dd, J= 8.1, 4.6 Hz, 1H), 7.73 (d, J= 9.1 Hz, 1H), 7.67 (d, J= 7.8 Hz, 1H), 7.52 (dd, J= 13.4, 7.7 Hz, 2H), 7.44 (d, J= 7.7 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.24 (s, 1H), 5.54 (q, J= 6.8 Hz, 1H), 5.11 (dd, J= 13.3, 5.1 Hz, 1H), 4.58 (s, 2H), 4.43 (d, J= 17.3 Hz, 1H), 4.31 (d, J= 17.2 Hz, 1H), 3.36 (s, 2H), 3.21 (d, J= 41.8 Hz, 2H), 2.91 (s, 4H), 2.66-2.55 (m, 1H), 2.52 (s, 4H), 2.42-2.31 (m, 1H), 2.01 (dd, J= 18.9, 8.9 Hz, 6H), 1.66 (d, J= 6.9 Hz, 3H); MS (ESI) m z: 780.3 [M+H]+.
Figure imgf000210_0002
[00432] 3-(5-(1-(3-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione
B007. 1H NMR (400 MHz, DMSO-d6) δ 10 .97 (s, 1H), 9.56-9.40 (m, 1H), 8.93 (s, 1H), 8.34- 8.19 (tn, 2H), 8.17 (s, 1H), 8.02 (d, J= 6.4 Hz, 1H), 7.67-7.57 (m, 3H), 7.55-7.37 (m, 4H), 7.28- 7.10 (m, 2H), 5.73 (t, .7 = 6.8 Hz, 1H), 5.15-5.04 (m, 1H), 4.49-4.22 (m, 2H), 3.73-3.61 (m, 2H), 3.06-2.98 (m, 2H), 2.97-2.82 (m, 2H), 2.77-2.73 (tn, 3H), 2.70-2.63 (m, 2H), 2.61 (d, J= 3.2 Hz, 1H), 2.19-2.10 (m, 2H), 2.04-1.95 (m, 1H), 1.84-1.72 (m, 3H), 1.67 (d, J= 6.8 Hz, 3H); MS (ESI) wk 748.3 [M+H]+.
Figure imgf000211_0001
[00433 ] 3 -(( 17?)- 1 -((7-(4-(3 -((4-(3-(2,6-Dioxopiperi din-3 -yl)- 1 -methyl- 1H-indazol-6-yl)- piperidin-l-yl)methyl)phenyl)piperazin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)- 2-methylbenzonitrile B052. 1H NMR (400 MHz, DMSO-d6) δ 10 .9 (s, 1H), 9.01 (s, 1H), 7.72 (d, .7= 7.6 Hz, 1H), 7.64-7.53 (m, 3H), 7.46 (d, ,7= 12.0 Hz, 2H), 7.35-7.29 (m, 1H), 7.23 (dd, J = 7.6, 7.6 Hz, 1H), 7.05 (d, J - 8 8 Hz, 1H), 7.00 (s, 1H), 6.94 (d, J= 8.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.59-5.48 (m, 1H), 4.32 (dd, J= 5.2, 9.5 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 4H), 3.49 (s, 2H), 3.30 (s, 6H), 2.93-2.90 (m, 2H), 2.66 (s, 3H), 2.56 (s, 3H), 2.38-2.31 (m, 2H), 2.20-2.14 (m, 1H), 2.11-2.04 (m, 2H), 1.83-1.74 (m, 4H), 1.55 (d, J= 7.2 Hz, 3H); MS (ESI) m/z: 802.3 [M+H]+.
Figure imgf000211_0002
[00434] 3-(( 1R)- 1 -((7-(3-((4-(3-(2,6-Dioxopiperidin-3-yl)- 1 -methyl- 17/-indazol-6-yl)- piperidin-l-yl)methyl)phenyl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methyl- benzonitrile B053. 1H NMR (400 MHz, DMSO-d6) δ 10 .87 (s, 1H), 9.49 (s, 1H), 8.90 (s, 1H), 8.28 (s, 1H), 8.21 (d, J= 7.6 Hz, 1H), 8.16 (s, 1H), 8.06 (d, .7= 6.8 Hz, 1H), 7.80 (d, J= 7.6 Hz, 1H), 7.61 (q, J= 7.6 Hz, 3H), 7.55-7.51 (m, 1H), 7.46 (s, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.66 (d, J= 4.8 Hz, 1H), 4.33 (dd, J= 5.2, 9.6 Hz, 1H), 4.00-3.94 (m, 3H), 3.68 (s, 2H), 3.03 (d, J= 10.8 Hz, 2H), 2.75 (s, 3H), 2.69 (s, 3H), 2.68-2.54 (m, 3H), 2.41-2.28 (m, 1H), 2.12 (s, 3H), 1.82 (s, 4H), 1.62 (d, J= 6.8 Hz, 3H); MS (ESI) m/r 718.3 [M+H]+.
Figure imgf000212_0001
[00435] 3-(l-Methyl-7-(1-(3-(4-methyl-1-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6- dione B054. 1H NMR (400 MHz, DMSO-d6) δ 10 .9 (s, 1H), 9.49 (s, 1H), 8.92 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 8.06 (d, J= 6.8 Hz, 1H), 7.79 (d, J= 8.0 Hz, 1H), 7.62-7.56 (m, 1H), 7.55-7.49 (m, 3H), 7.36-7.25 (m, 2H), 7.06 (dd, J = 7.6, 7.6 Hz, 1H), 5.71 (dd, J = 6.8, 6.8 Hz, 1H), 4.34 (dd, J= 5.2, 10.0 Hz, 1H), 4.21 (s, 3H), 3.70 (s, 2H), 3.05 (d, J= 11.2 Hz, 2H), 2.74 (s, 3H), 2.68-2.61 (m, 2H), 2.59 (s, 3H), 2.39-2.21 (m, 4H), 2.20-2.10 (m, 1H), 1.96-1.75 (m, 4H), 1.61 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 761.4 [M+H]+.
Figure imgf000212_0002
[00436] 3 -(6-( 1 -(3 -( 1 -(( (R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3, 4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-l -methyl- 1H-indazol-3-yl)piperidine-2, 6- dione B055. 1H NMR (400 MHz, DMSO-d6) δ 10 .86 (s, 1H), 9.51 (s, 1H), 8.93 (s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.22 (d, J= 7.6 Hz, 1H), 8.02 (d, J= 6.8 Hz, 1H), 7.65 (t, J= 7.6 Hz, 1H), 7.62-7.57 (m, 2H), 7.55-7.51 (m, 1H), 7.50-7.47 (m, 1H), 7.46 (s, 1H), 7.40-7.11 (m, 2H), 7.05 (d, J= 8.4 Hz, 1H), 5.73 (t, J= 6.8 Hz, 1H), 4.32 (dd, J= 4.8, 9.6 Hz, 1H), 3.96 (s, 3H), 3.67 (s, 2H), 3.03 (d, J= 11.6 Hz, 2H), 2.75 (s, 3H), 2.70-2.64 (m, 2H), 2.63-2.57 (m, 1H), 2.36-2.30 (m, 1H), 2.20-2.10 (m, 3H), 1.87-1.76 (m, 4H), 1.67 (d, J= 6.8 Hz, 3H); MS (ESI) m/r 747.4 [M+H]+.
Figure imgf000213_0001
[00437] 3 -(( 1R)- 1 -((7-(3 -((4-(3 -(2,6-Dioxopiperidin-3-yl)- 1 -methyl- 1H-indazol-7-yl)- piperidin-l-yl)methyl)phenyl)-4-methylpyrido[3,4-7]pyridazin-l-yl)amino)ethyl)-2 -methylbenzonitrile B056. 1H NMR (400 MHz, DMSO-d6) δ 10 .88 (s, 1H), 9.48 (s, 1H), 8.90 (s, 1H), 8.30-8.26 (m, 1H), 8.21 (d, 7= 8.0 Hz, 1H), 8.15 (s, 1H), 8.06 (d, 7= 6.8 Hz, 1H), 7.81-7.77 (m, 1H), 7.65-7.55 (m, 2H), 7.55-7.50 (m, 2H), 7.35-7.26 (m, 2H), 7.06 (t, J= 7.6 Hz, 1H), 5.67-5.52 (m, 1H), 4.34 (dd, 7= 5.2, 10.0 Hz, 1H), 4.26-4.16 (m, 3H), 3.78-3.63 (m, 2H), 3.05 (d, J= 10.8 Hz, 2H), 2.74 (s, 3H), 2.68 (s, 3H), 2.66-2.56 (m, 2H), 2.40-2.31 (m, 1H), 2.26 (t, J= 10.8 Hz, 2H), 2.19-2.11 (m, 1H), 1.95-1.75 (m, 4H), 1.61 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 718.3 [M+H]+.
Figure imgf000213_0002
[00438] 3-(7-(1-(5-(l -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-17/-indazol-3-yl)- piperidine-2, 6-dione B057. 1H NMR (400 MHz, DMSO-d6) δ 10 .89 (s, 1H), 9.50 (s, 1H), 8.92 (s, 1H), 8.41 (dd, J= 2.0, 7.2 Hz, 1H), 8.34-8.24 (m, 1H), 8.17 (s, 1H), 8.01 (d, J= 6.8 Hz, 1H), 7.64 (t, J= 7.6 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 7.51-7.43 (m, 2H), 7.40-7.10 (m, 3H), 7.05 (t, J = 7.6 Hz, 1H), 5.78-5.66 (m, 1H), 4.34 (dd, 7= 5.2, 9.6 Hz, 1H), 4.20 (s, 3H), 3.78-3.69 (m, 2H), 3.06 (d, 7 = 10.8 Hz, 2H), 2.74 (s, 3H), 2.71-2.53 (m, 3H), 2.36-2.26 (m, 3H), 2.20-2.10 (m, 1H), 1.96-1.87 (m, 2H), 1.81 (q, 7= 11.6 Hz, 2H), 1.66 (d, 7= 7.2 Hz, 3H); MS (ESI) m/z: 765.3 [M+H]+.
Figure imgf000214_0001
[00439] (R)-3 -(6-( 1 -(5 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)-3- methylpiperidine-2, 6-dione B058. 1H NMR (400 MHz, DMSO-d6) δ 10 .83 (s, 1H), 9.50 (s, 1H), 8.91 (s, 1H), 8.40 (dd, J= 2.0, 7.2 Hz, 1H), 8.31-8.25 (m, 1H), 8.03-7.94 (m, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.64 (t, J= 7.6 Hz, 1H), 7.49-7.44 (m, 3H), 7.34-7.15 (m, 2H), 7.12-7.03 (m, 1H),
5.72 (t, J= 6.8 Hz, 1H), 3.94 (s, 3H), 3.70 (s, 2H), 3.04 (d, J= 11.2 Hz, 2H), 2.89 (s, 1H), 2.75-
2.73 (m, 3H), 2.69-2.63 (m, 1H), 2.59-2.54 (m, 1H), 2.40-2.32 (m, 1H), 2.24-2.16 (m, 2H), 2.15- 2.06 (m, 1H), 1.80 (s, 4H), 1.66 (d, J= 7.2 Hz, 3H), 1.62 (s, 3H); MS (ESI) m/z: 779.2 [M+H]+.
Figure imgf000214_0002
[00440] (R)- 1 -( 6-( 1 -(5 -( 1 -(( 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl- 1H-indazol-3- yl)dihydropyrimidine-2, 4(1H,3H)-dione B091. MS (ESI) m/z: 766.3 [M+H]+.
Figure imgf000214_0003
[00441 ] 3 -(4-( 1 -(3 -( 1 -(( (R)- 1 -(3 - Amino-5 -(trifluoromethyl)phenyl)ethyl)amino)-4-rnethyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B102. 1H NMR (400 MHz, DMSO-<A) δ 10 .8 (s, 1H), 9.50 (d, J = 1 .0 Hz, 1H), 8.90 (s, 1H), 8.27 (d, J = 1.7 Hz, 1H), 8.24-8.18 (m, 1H), 7.91 (d, J = 13 Hz, 1H), 7.57 (d, J = 7.6, 7.6 Hz, 1H), 7.50 (d, J= 7.6 Hz, 1H), 7.24-7.18 (m, 2H), 7.15-7.10 (m, 2H), 6.87 (d, J= 5.5 Hz, 2H), 6.68 (dd, J= 2.0, 2.0 Hz, 1H), 5.50 (s, 2H), 5.43 (p, J= 7.1 Hz, 1H), 3.80 (dd, J= 11.4, 4.9 Hz, 1H), 3.64 (s, 2H), 2.99 (d, J= 10.9 Hz, 2H), 2.76 (s, 3H), 2.65 (ddd, J= 17.1, 11.7, 5.3 Hz, 1H), 2.51-2.43 (m, 1H), 2.22-2.10 (m, 3H), 2.08 (s, 2H), 2.06-1.97 (m, 1H), 1.79-1.62 (m, 3H), 1.61 (d, J= 7.1 Hz, 3H); MS (ESI) m/z: 708.3 [M+H]+.
Figure imgf000215_0001
[00442] 3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 - Amino-5 -(trifluoromethyl)phenyl)ethyl)amino)-4-rnethyl- pyrido[3,4-d]pyridazin-7-yl)phenethyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B103. MS
(ESI) m/z. 722.3
Figure imgf000215_0002
[00443] 3-(4-(4-(3-(1-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)phenethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B104. MS (ESI) m/z: 1233 [M+H]+.
Figure imgf000216_0001
[00444] 3-(4-(4-(3-(1-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B105. MS (ESI) m z-. 709.3 [M+H]+.
Figure imgf000216_0002
[00445 ] 3 -(4-( 1 -(((R)-4-( 1 -(((/()- 1 -(3 - Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)- piperidine-2, 6-dione B106. 1H NMR (400 MHz, DMSO-d6) δ 10 .8 (s, 1H), 9.03 (s, 1H), 7.45- 7.35 (m, 2H), 7.20 (d, J= 7.8 Hz, 1H), 7.03-6.93 (m, 2H), 6.82 (br s, 2H), 6.66 (s, 1H), 5.49 (s, 2H), 5.34 (quin, J = 7.2 Hz, 1H), 4.51 (br d, J= 12.8 Hz, 1H), 4.25 (br d, J= 12.8 Hz, 1H), 4.04 (br d, J= 9.8 Hz, 1H), 3.80-3.58 (m, 3H), 3.11-3.01 (m, 3H), 2.77 (br dd, J= 10.6, 12.9 Hz, 1H), 2.69-2.60 (m, 2H), 2.58 (s, 3H), 2.52 (br d, J= 4.0 Hz, 2H), 2.46-2.43 (m, 1H), 2.28 (s, 3H), 2.21-2.09 (m, 3H), 2.04-1.98 (m, 1H), 1.68 (br s, 4H), 1.55 (d, J= 7.2 Hz, 3H); MS (ESI) m/z: 731.6 [M+H]+.
Figure imgf000217_0001
[00446] 3-(4-(2-(5-(1-(((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-oxopyridin-1( 2H)-yl)ethyl)phenyl)piperidine-2, 6-dione B107. MS (ESI) m/z. 656.2
Figure imgf000217_0002
[00447] 3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethy l)-2-fluoropheny l)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B108. 1 H NMR (400 MHz, DMSO-d6) δ 10 .8 (s, 1H), 9.71 (s, 1H), 9.20 (s, 1H), 8.56 (d, J= 1.8 Hz, 1H), 8.45 (ddd, ,/= 7.6, 1.6, 1.6 Hz, 1H), 7.83-7.74 (m, 2H), 7.71 (dd, ./= 7.5, 7.5 Hz, 1H), 7.54 (dd, J = 7.1, 7.1 Hz, 1H), 7.29 (dd, J = 7.7, 7.7 Hz, 1H), 7.25 (s, 1H), 7.19 (s, 4H), 5.63 (p, J= 6.9 Hz, 1H), 4.53 (s, 1H), 4.28-4.18 (m, 1H), 4.13 (ddd, J= 11.9, 6.5, 5.5 Hz, 1H), 3.82 (dd, J= 11.6, 5.0 Hz, 1H), 3.17 (d, J= 11.8 Hz, 2H), 2.88 (s, 3H), 2.88-2.79 (m, OH), 2.66 (ddd, J= 17.2, 11.9, 5.4 Hz, 1H), 2.46 (t, .7= 4.2 Hz, 1H), 2.29 (t, J= 7.3 Hz, 1H), 2.21-2.10 (m, 1H), 2.06-1.96 (m, 2H), 1.89 (td, J= 13.6, 10.2 Hz, 2H), 1.71 (d, J= 7.0 Hz, 3H), 1.48 (d, J= 18.2 Hz, 1H), 0.88-0.82 (m, 2H); MS (ESI) m/z: 693.3 [M+H]+.
Figure imgf000218_0001
[00448] 3-(( 1R)-1-((7-(3-((4-(4-(2,6-Dioxopiperidin-3-yl)phenyl)piperidin-l-yl)methyl)- phenyl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile B109. 1H NMR (400 MHz, DMSO--ds) δ 10 .8 (s, 1H), 9.75 (s, 1H), 9.24 (s, 1H), 8.57 (s, 1H), 8.45 (dq, J= 8.4, 2.9 Hz, 1H), 7.83 (dd, J= 7.9, 1.3 Hz, 1H), 7.80-7.76 (m, 2H), 7.68 (dd, J= 7.7, 1.3 Hz, 1H), 7.36 (t, J= 7.8 Hz, 1H), 7.19 (s, 4H), 5.46 (p, J= 6.8 Hz, 1H), 4.55-4.51 (m, 2H), 3.82 (dd, J= 11.6, 5.0 Hz, 1H), 3.54 (d, J= 11.5 Hz, 2H), 3.17 (d, J= 11.0 Hz, 2H), 2.92 (s, 3H), 2.82 (ddd, J= 19.6, 13.4, 5.1 Hz, 1H), 2.69 (s, 3H), 2.67-2.60 (m, 1H), 2.51-2.44 (m, 2H), 2.22-2.10 (m, 1H), 2.05-1.96 (m, 3H), 1.96-1.85 (m, 2H), 1.66 (d, J= 6.9 Hz, 3H); MS (ESI) m/z: 664.3 [M+H]+.
Figure imgf000218_0002
[00449] 3 -(4-( 1 -(3 -(4-Methy 1- 1 -(((R)- 1 -(2-methyl -3 -(trifluoromethyl)pheny l)ethy 1)- amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 10. 1H NMR (400 MHz, DMSO-d6) δ 10 .82 (s, 1H), 9.70 (s, 1H), 9.20 (s, 1H), 8.57 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 7.84-7.74 (m, 3H), 7.58 (d, J= 7.8 Hz, 1H), 7.44-7.33 (m, 1H), 7.19 (s, 4H), 5.60 (t, J= 6.9 Hz, 1H), 4.53 (s, 2H), 3.82 (dd, J= 11.6, 5.0 Hz, 1H), 3.52 (s, 1H), 3.17 (d, J= 12.0 Hz, 2H), 2.88 (s, 3H), 2.86-2.78 (m, 1H), 2.66 (ddd, J= 17.2, 11.9, 5.3 Hz, 1H), 2.59 (s, 3H), 2.54 (s, 2H), 2.47 (d, J= 4.2 Hz, 1H), 2.16 (qd, J= 12.3, 4.4 Hz, 1H), 2.06-1.97 (m, 3H), 1.89 (q, J = 11.6 Hz, 2H), 1.66 (d, J= 6.9 Hz, 3H); MS (ESI) m/z: 707.3 [M+H]+.
Figure imgf000219_0001
[00450] 3 -(4-( 1 -(2-(5-( 1 -(((R)- 1 -(3 -Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-oxopyridin-l(2H)-yl)ethyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione Bill. MS (ESI) m .2: 739.3 [M+H]+.
Figure imgf000219_0002
[00451] 3-(4-(1-(3-(l -(((R)- 1 -(3 -(Difluoromethy l)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-5-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B112. MS (ESI) m/z: 711.3 [M+H]+.
Figure imgf000219_0003
[00452] 3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)-4-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B113. MS (ESI) m/z: 711.2 [M+H]+.
Figure imgf000220_0001
[00453] 3-(4-(1-(5-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 14. 1H NMR (400 MHz, DMSO-d6) δ 10 .8 (s, 1H), 9.73 (s, 1H), 9.20 (s, 1H), 8.70 (dd, J= 7.2, 2.4 Hz, 1H), 8.52 (ddd, J= 7.9, 4.8, 2.4 Hz, 1H), 7.75-7.68 (m, 2H), 7.55 (t, J= 7.1 Hz, 1H), 7.30 (t, J= 7.7 Hz, 1H), 7.25 (s, 1H), 7.18 (s, 4H), 5.62 (q, J= 6.9 Hz, 1H), 4.59-4.55 (m, 2H), 3.82 (dd, J= 11.6, 5.0 Hz, 1H), 3.62-3.54 (m, 2H), 3.27 (d, J= 11.6 Hz, 3H), 2.90 (s, 3H), 2.88-2.79 (m, 1H), 2.66 (td, J= 11.7, 5.9 Hz, 1H), 2.46 (t, J= 4.3 Hz, 1H), 2.16 (qd, J= 12.4, 4.4 Hz, 1H), 2.10-1.97 (m, 3H), 1.89 (q, J= 13.0 Hz, 2H), 1.72 (d, J= 6.9 Hz, 3H); MS (ESI) m/z: 711.3 [M+H]+.
Figure imgf000220_0002
[00454] 3-(4-(1-(3-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-rnethyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 15. 1H NMR (400 MHz, DMSO-d6) δ 10 .8 (s, 1H), 9.79 (s, 1H), 9.02 (s, 1H), 8.12 (td, J= 7.6, 1.8 Hz, 1H), 7.90-7.83 (m, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.54 (t, J = 7.1 Hz, 1H), 7.29 (t, J= 7.7 Hz, 1H), 7.25 (s, 1H), 7.19 (s, 4H), 5.60 (p, J= 6.9 Hz, 1H), 4.56 (s, 2H), 3.82 (dd, J= 11.6, 5.0 Hz, 1H), 3.61-3.58 (m, 4H), 3.24 (s, 2H), 2.91 (s, 3H), 2.89-2.79 (m, 1H), 2.66 (ddd, J=
Figure imgf000220_0003
11.9, 5.3 Hz, 1H), 2.47 (t, J= 4.2 Hz, 1H), 2.16 (qd, J= 12.4, 4.4 Hz, 1H), 2.06-1.97 (m, 3H), 1.92 (q, J= 13.7 Hz, 1H), 1.68 (d, J= 7.0 Hz, 3H); MS (ESI) m/z: 711.2 [M+H]+.
Figure imgf000221_0001
[00455] 3 -(4-(l -(3 -(1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-m ethyl- pyrido[3,4-d ]pyridazin-7-yl)-5-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 16.
MS (ESI) m/z. 707.3 [M+H]+.
Figure imgf000221_0002
[00456] 3 -(4-( 1 -(5-(l -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 17. MS (ESI) m/z: 707.3 [M+H]+.
Figure imgf000221_0003
[00457] 3-(4-(1-(3-(l -(((R)- 1 -(3 -(Difluoromethy l)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-4-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 18. MS (ESI) m/z: 707.3 [M+H]+.
Figure imgf000222_0001
[00458] 3 -(4-( 1 -(3 -(1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 19. MS (ESI) m/z. 707.3 [M+H]+.
Figure imgf000222_0002
[00459] 3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethy l)-2-fluoropheny l)ethyl)amino)-4-methy 1- pyrido[3,4-d]pyridazin-7-yl)phenethyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B120. MS (ESI) m/z: 707.3 [M+H]+.
Figure imgf000222_0003
[00460] 3 -(4-( 1 -(2-Chl oro-5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-
4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B121. 1H NMR (400 MHz, DMSO-d6) δ 10 .8 (s, 1H), 9.67 (s, 2H), 9.19 (s, 1H), 8.77 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 7.95 (d, J= 8.5 Hz, 1H), 7.70 (t, J= 1A Hz, 1H), 7.53 (t, J= 7.2 Hz, 1H), 7.29 (t, J= 7.7 Hz, 1H), 7.25 (s, OH), 7.18 (s, 3H), 5.68-5.62 (m, 1H), 4.67 (s, 2H), 3.82 (dd, J= 11.6, 5.0 Hz, 1H), 3.58 (s, 3H), 2.87 (s, 4H), 2.71 -2.60 (m, 2H), 2.47 (d, J= 4.2 Hz, 2H), 2.39-2.34 (m, 2H), 2.20-2.11 (m, 1H), 2.01 (s, 3H), 1.92 (d, J= 13.0 Hz, 1H), 1.71 (d, J= 7.0 Hz, 3H); MS (ESI) m/z: 727.2 [M+H]+.
Figure imgf000223_0001
[00461] 2-Methyl-3-((R)-1-((4-methyl-7-(3-((4-(4-( (R)-3-methyl-2,6-dioxopiperidin-3-yl)- phenyl)piperidin-l-yl)methyl)phenyl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile B122. 1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.48 (s, 1H), 8.90 (s, 1H), 8.28 (s, 1H), 8.22 (br d, J= 7.6 Hz, 1H), 8.14 (s, 1H), 8.06 (br d, J= 6.8 Hz, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.65-7.55 (m, 2H), 7.54-7.49 (m, 1H), 7.32 (t, J= 8.0, 8.0 Hz, 1H), 7.28-7.23 (m, 2H), 7.22-7.16 (m, 2H), 5.65-5.56 (m, 1H), 3.73 (br s, 2H), 3.03 (br d, J= 10.8 Hz, 2H), 2.74 (s, 3H), 2.68 (s, 3H), 2.54 (br s, 1H), 2.43 (br dd, J= 3.6, 13.1 Hz, 1H), 2.37-2.30 (m, 1H), 2.20 (br d, J= 7.6 Hz, 2H), 2.12-1.97 (m, 2H), 1.82-1.66 (m, 4H), 1.60 (d, J= 6.8 Hz, 3H), 1.41 (s, 3H); MS (ESI) m/z: 678.4 [M+H]+.
Figure imgf000223_0002
[00462] (R)-3 -Methyl-3 -(4-( 1 -(3 -(4-m ethyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethyl)- phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B123. 1H NMR (400 MHz, DMSO-d6) δ 10 .9 (s, 1H), 9.48 (s, 1H), 8.92 (s, 1H), 8.31 (s, 1H), 8.25 (d, J= 7.6 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J= 6.8 Hz, 1H), 7.79 (d, J= 7.6 Hz, 1H), 7.67-7.57 (m, 1H), 7.53 (d, J= 8.0 Hz, 2H), 7.32 (dd, J= 7.6, 7.6 Hz, 1H), 7.28-7.23 (m, 2H), 7.23-7.17 (m, 2H), 5.71 (quin, J= 6.8 Hz, 1H), 3.97-3.56 (m, 2H), 3.16-3.00 (m, 2H), 2.74 (s, 3H), 2.59 (s, 4H), 2.43-2.40 (m, 1H), 2.37-2.30 (m, 2H), 2.16-1.92 (m, 3H), 1.86-1.67 (m, 4H), 1.61 (d, J= 7.2 Hz, 3H), 1.41 (s, 3H); MS (ESI) m/z: 721.3 [M+H]+.
Figure imgf000224_0001
[00463] 2-Methyl-3-((R)-1-((4-methyl-7-(3-((4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)- phenyl)piperidin-l-yl)methyl)phenyl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile
B124. 1H NMR (400 MHz, DMSO-d6) δ 10.9 (s, 1H), 9.48 (s, 1H), 8.89 (s, 1H), 8.26 (s, 1H),
8.20 (br d, J= 7.6 Hz, 1H), 8.14 (s, 1H), 8.06 (br d, J= 6.8 Hz, 1H), 7.78 (d, J= 7.2 Hz, 1H), 7.64-7.55 (m, 2H), 7.50 (br d, J= 8.0 Hz, 1H), 7.32 (br d, J= 8.0, 8.0 Hz, 1H), 7.28-7.23 (m, 2H), 7.22-7.15 (m, 2H), 5.67-5.55 (m, 1H), 3.66 (br s, 2H), 2.99 (br d, J= 10.0 Hz, 2H), 2.73 (s, 3H), 2.68 (s, 3H), 2.55-2.53 (m, 1H), 2.42 (br d, J= 3.2 Hz, 1H), 2.32 (br d, J= 3.6 Hz, 1H),
2.18-2.06 (m, 3H), 2.05-2.01 (m, 1H), 1.80-1.67 (m, 4H), 1.60 (d, J= 7.2 Hz, 3H), 1.41 (s, 3H);
MS (ESI) m/z: 678.4 [M+H]+.
Figure imgf000224_0002
[00464] (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-2, 6-dione B125. 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.50 (s, 1H), 8.94 (s, 1H), 8.27 (s, 1H), 8.22 (d, J= 8.0 Hz, 1H), 8.05 (d, J= 6.8 Hz, 1H), 7.74-7.63 (m, 1H), 7.61-7.55 (m, 1H), 7.54- 7.45 (m, 2H), 7.40-7.11 (m, 6H), 5.90-5.60 (m, 1H), 3.64 (s, 2H), 2.98 (d, J= 10.0 Hz, 2H), 2.74 (s, 3H), 2.66-2.57 (m, 1H), 2.45 (s, 2H), 2.16-2.00 (m, 4H), 1.81-1.68 (m, 4H), 1.66 (d, J= 6.9 Hz, 3H), 1.41 (s, 3H); MS (ESI) m/z: 707.4 [M+H]+.
Figure imgf000225_0001
[00465] (R)-3-(4-(l -(5-(l -(((R)- 1 -(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-
2,6-dione B126. MS (ESI) m/z: 725.3 [M+H]+.
Figure imgf000225_0002
[00466] (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B127. 1H NMR (400 MHz, DMSO-d6) δ 10 .91 (s, 1H), 9.76 (s, 1H), 9.23 (s, 1H), 8.70 (dd, J = 1.2, 2.4 Hz, 1H), 8.53 (ddd, J = 8.8, 4.9, 2.4 Hz, 1H), 7.72 (td, J = 8.5, 5.0 Hz, 2H), 7.55 (t, J= 7.1 Hz, 1H), 7.31 (t, .7 = 7.7 Hz, 1H), 7.27-7.20 (m, 5H), 5.60 (p, J= 6.9 Hz, lH), 4.57 (s, 2H), 3.61-3.55 (m, 3H), 3.25 (s, 2H), 2.92 (s, 3H), 2.89-2.78 (m, 1H), 2.48-2.41 (m, 1H), 2.38- 2.30 (m, 1H), 2.13-1.97 (m, 4H), 1.88 (q, J= 13.1 Hz, 2H), 1.72 (d, .7 = 7.0 Hz, 3H), 1.41 (s, 3H); MS (ESI) m/z: 725.3 [M+H]+.
Figure imgf000225_0003
[00467] (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B128. 1H NMR (400 MHz, DMSO-d6) δ 10 .91 (s, 1H), 9.75 (s, 1H), 9.24 (s, 1H), 8.69 (dd, J= 7.1, 2.4 Hz, 1H), 8.52 (ddd, J= 7.8, 4.9, 2.4 Hz, 1H), 7.74-7.65 (m, 2H), 7.44 (d, J= 7.7 Hz, 1H), 7.36-7.19 (m, 6H), 5.54 (p, J= 6.9 Hz, 1H), 4.57 (s, 2H), 3.58 (d, J= 11.5 Hz, 2H), 3.25 (s, 2H), 2.92 (s, 3H), 2.87-2.80 (m, 1H), 2.52 (s, 3H), 2.48-2.41 (m, 1H), 2.37-2.30 (m, 1H), 2.13-1.98 (m, 5H), 1.89 (t, J= 13.4 Hz, 2H), 1.66 (d, J= 6.9 Hz, 3H), 1.41 (s, 3H); MS (ESI) m z. 721.3 [M+H]+.
Figure imgf000226_0001
[00468] (R)-3 -(4-( 1 -(2-Fluoro-5-( 1 -(((R)- 1 -(3 -fluoro-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-2, 6-dione B129. 1H NMR (400 MHz, DMSO-d6) δ 10 .91 (s, 1H), 9.74 (s, 1H), 9.21 (s, 1H), 8.71-8.66 (m, 1H), 8.51 (d, ,. J = 5.5 Hz, 1H), 7.72 (t, J= 9.0 Hz, 1H), 7.31 (q, .7= 7.0 Hz, 1H), 7.27-7.16 (m, 5H), 7.04 (t, J = 7.6 Hz, 1H), 5.61-5.54 (m, 1H), 4.57 (s, 2H), 3.36-3.05 (m, 5H), 2.90 (s, 3H), 2.88-2.79 (m, 1H), 2.48-2.41 (m, 1H), 2.37-2.30 (m, 1H), 2.26 (d, J= 1.9 Hz, 3H), 2.14-1.98 (m, 4H), 1.87 (q, J= 13.2 Hz, 2H), 1.70 (d, J= 6.9 Hz, 3H), 1.41 (s, 3H); MS (ESI) m/z: 689.3 [M+H]+.
Figure imgf000226_0002
[00469] 3-(4-(1-(5-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2,6- dione B130. 1H NMR (400 MHz, DMSO-d6) δ 10 .8 (s, 1H), 10.04-9.87 (m, 1H), 9.71 (s, 1H), 9.21 (s, 1H), 9.05-8.87 (m, 1H), 8.70 (br d, J= 5.6 Hz, 1H), 8.52 (dt, J= 2.4, 5.6 Hz, 1H), 7.75- 7.65 (m, 2H), 7.54 (br dd, J= 12, 7.2 Hz, 1H), 7.39-7.12 (m, 2H), 7.11-6.99 (m, 3H), 5.63 (quin, .7= 6.8 Hz, 1H), 4.57 (br s, 2H), 3.76 (br dd, J= 4.8, 11.2 Hz, 1H), 3.59 (br d, J= 11.6 Hz, 1H), 3.30 (br s, 2H), 3.04 (br dd, J= 4.4, 9.2 Hz, 1H), 2.89 (s, 3H), 2.64 (dd, J= 5.4, 5.4, 11.6 Hz, 1H), 2.46 (br d, J= 4.4 Hz, 2H), 2.31 (s, 3H), 2.14 (dt, J= 8.4, 12.0 Hz, 1H), 2.04-1.86 (m, 5H), 1.72 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 725.1 [M+H]+.
Figure imgf000227_0001
[00470] 3-(4-(1-(5-(l -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)piperidine-2, 6-dione B131 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.50 (s, 1H), 8.91 (s, 1H), 8.39 (dd, J= 2.0, 6.8 Hz, 1H), 8.31-8.24 (m, 1H), 8.18 (s, 1H), 8.00 (d, J= 6.8 Hz, 1H), 7.64 (br t, J= 7.2 Hz, 1H), 7.52-7.42 (m, 2H), 7.40-7.10 (m, 3H), 7.06-6.96 (m, 2H), 5.72 (quin, J= 12 Hz, 1H), 3.85 (dd, J= 4.8, 11.6 Hz, 1H), 3.69 (s, 2H), 3.02 (br d,
Figure imgf000227_0002
11.2 Hz, 2H), 2.84-2.76 (m, 1H), 2.74 (s, 3H), 2.69-2.60 (m, 1H), 2.48-2.44 (m, 1H), 2.25-2.13 (m, 3H), 2.05-1.95 (m, 1H), 1.74 (br s, 4H), 1.66 (d, J= 6.8 Hz, 3H); MS (ESI) m/z: 1292 [M+H]+.
Figure imgf000227_0003
[00471] 3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluoropheny l)ethy l)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)- piperidine-2, 6-dione B132. 1H NMR (400 MHz, DMSO-d6) δ 10 .81 (s, 1H), 9.03 (s, 1H), 8.16 (s, 1H), 7.61-7.51 (m, 2H), 7.49-7.43 (m, 2H), 7.41-7.15 (m, 3H), 7.12-6.97 (m, 2H), 5.64 (q, J = 6.8 Hz, 1H), 4.53 (d, J= 12.6 Hz, 1H), 4.26 (d, J= 12.6 Hz, 1H), 4.06 (d, 7= 9.6 Hz, 1H), 3.75 (dd, .7= 4.8, 11.2 Hz, 2H), 3.70-3.62 (m, 1H), 3.13-3.04 (m, 3H), 2.79 (dd, J= 10.7, 12.7 Hz, 1H), 2.72-2.57 (m, 4H), 2.56 (s, 3H), 2.47-2.32 (m, 1H), 2.29 (s, 3H), 2.27-2.10 (m, 3H), 2.07- 1.96 (m, 1H), 1.74-1.65 (m, 4H), 1.60 (d, J= 7.2 Hz, 3H); MS (ESI) m/z: 716.4 [M+H]+.
Figure imgf000228_0001
[00472] -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B133. 1H NMR (400 MHz, DMSO-d6) δ 10 .91 (s, 1H), 9.82 (s, 1H), 9.05 (s, 1H), 8.12 (td, J= 7.6, 1.8 Hz, 1H), 7.91-7.84 (m, 1H), 7.69 (t, J= 7.5 Hz, 1H), 7.58 (dt, J= 30.8, 7.4 Hz, 2H), 7.33-7.20 (m, 6H), 5.59 (p, J= 6.9 Hz, 1H), 4.55 (s, 2H), 3.59-3.56 (m, 3H), 3.23 (s, 2H), 2.92 (s, 3H), 2.89-2.77 (m, 1H), 2.48-2.41 (m, 1H), 2.38-2.30 (m, 1H), 2.13-1.98 (m, 4H), 1.97- 1.86 (m, 2H), 1.68 (d, .7 = 7.0 Hz, 3H), 1.41 (s, 3H); MS (ESI) m/z: 725.3 [M+H]+.
Figure imgf000228_0002
[00473 ] (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fIuorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-5-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B134. MS (ESI) m/z: 725.3 [M+H]+.
Figure imgf000229_0001
[00474] (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-4-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B135. MS (ESI) m/z: 725.3 [M+H]+.
Figure imgf000229_0002
[00475] (R)-3-(4-(1-(((R)-4-(1-(( (R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)- 4-methylpyrido[3,4-d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B136. 1H NMR (400 MHz, DMSO-d6) δ 10 .92 (s, 1H), 9.32 (s, 1H), 7.71 (s, 1H), 7.62 (t, J= 7.5 Hz, 1H), 7.54 (t, J= 7.1 Hz, 1H), 7.40-7.23 (m, 6H), 5.48 (p, J= 6.9 Hz, 1H), 4.71 (s, 1H), 4.41 (s, 1H), 4.20-4.14 (m, 1H), 4.14-4.07 (m, 1H), 3.84-3.75 (m, 1H), 3.70-
3.61 (m, 2H), 3.38-3.27 (m, 3H), 3.21-2.97 (m, 3H), 2.83 (s, 1H), 2.77 (s, 2H), 2.50-2.42 (m, 3H), 2.40-2.30 (m, 1H), 2.15-1.82 (m, 6H), 1.66 (d, J= 7.0 Hz, 3H), 1.43 (s, 3H); MS (ESI) m/z: 716.3 [M+H]+.
Figure imgf000229_0003
[00476] (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethy l)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2,6-dione B137. 1H NMR (400 MHz, DMSO-d6) δ 10 .93-10.77 (m, 2H), 9.94 (s, 1H), 9.81 (s, 1H), 8.99 (s, 1H), 8.61-8.52 (m, 1H), 7.97 (t, J= 6.8 Hz, 1H), 7.86 (d, J= 7.6 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H), 7.58-7.51 (m, 1H), 7.40-7.12 (m, 3H), 7.11-7.05 (m, 2H), 5.73-5.57 (m, 1H), 4.52 (d, J= 3.6 Hz, 2H), 3.52 (s, 3H), 3.26-3.14 (m, 2H), 3.07-2.99 (m, 1H), 2.96 (s, 3H), 2.43 (d, J= 13.6 Hz, 1H), 2.31 (s, 3H), 2.19 (d, J= 12.4 Hz, 2H), 2.10-2.02 (m, 2H), 1.89 (d, J= 12.8 Hz, 2H), 1.82 (d, J= 6.8 Hz, 3H), 1.39 (s, 3H); MS (ESI) m/z: 721.2 [M+H]+.
Figure imgf000230_0001
[00477] (R)-3-(4-(l -(5-(l -(((R)-! -(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B138. MS (ESI) /» z: 735.3 [M+H]+.
Figure imgf000230_0002
[00478] (R)-3 -(4-(l -(5-( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B139. 1H NMR (400 MHz, DMSO-d6) δ 10 .85 (s, 1H), 9.50 (s, 1H), 8.91 (s, 1H), 8.45-8.34 (m, 1H), 8.32-8.22 (m, 1H), 8.00 (d, J= 6.8 Hz, 1H), 7.65 (t, J= 7.2 Hz, 1H), 7.52-7.42 (m, 2H), 7.39-7.11 (m, 3H), 7.09-6.97 (m, 2H), 5.77-5.68 (m, 1H), 3.69 (s, 2H), 3.01 (d, J= 10.8 Hz, 2H), 2.74 (s, 3H), 2.70-2.61 (m, 1H), 2.44-2.32 (m, 2H), 2.31-2.25 (m, 3H), 2.23-2.14 (m, 2H), 2.12-1.98 (m, 2H), 1.67 (d, J= 6.8 Hz, 7H), 1.39 (s, 3H); MS (ESI) m/z:
739.3 [M+H] 1.
Figure imgf000231_0001
[00479] (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B140. 1H NMR (400 MHz, DMSO-d6) δ 10 .87 (s, 1H), 9.49 (s, 1H), 8.91 (s, 1H), 8.41 (dd, J= 2.0, 7.2 Hz, 1H), 8.33-8.23 (m, 1H), 8.00 (d, J= 6.8 Hz, 1H), 7.64 (t, J= 7.6 Hz, 1H), 7.52-7.42 (m, 2H), 7.40-7.18 (m, 2H), 7.15-6.98 (m, 3H), 5.72 (q, J
= 6.8 Hz, 1H), 5.56 (s, 1H), 3.78 (s, 2H), 3.15 (d, J= 2.0 Hz, 2H), 2.76-2.69 (m, 5H), 2.48-2.34 (m, 2H), 2.34-2.29 (m, 2H), 2.24 (s, 3H), 2.12-2.00 (m, 2H), 1.66 (d, J= 7.2 Hz, 3H), 1.40 (s, 3H); MS (ESI) m/z: 737.4 [M+H]+.
Figure imgf000231_0002
[00480] (R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)furan-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B141. 1H NMR (400 MHz, DMSO-d6) δ 10 .87 (s, 1H), 9.37 (s, 1H), 8.60 (s, 1H), 8.40 (s, 1H), 7.79 (d, J= 6.9 Hz, 1H), 7.63 (t, J= 7.5 Hz, 1H), 7.48 (t, J= 7.1 Hz, 1H), 7.28-7.22 (m, 2H), 7.21 (s, 1H), 7.10 (s, 1H), 7.05 (s, 2H), 5.70 (p, .7 = 7.0 Hz, 1H), 3.66 (s, 2H), 3.33 (s, 3H), 3.03 (s, 2H), 2.71 (s, 3H), 2.48-2.39 (m, 1H), 2.37-2.30 (m, 1H), 2.28 (s, 3H), 2.19 (s, 1H), 2.08-1.98 (m, 1H), 1.66 (d, J= 7.0 Hz, 7H), 1.40 (s, 3H); MS (ESI) m/z: 711.3 [M+H]+.
Figure imgf000232_0001
[00481] (3 R) - 3 -(4-(8-(((R)-4-( 1 -(((R)- 1 -(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-
4-methylpyrido[3,4-<i]pyridazin-7-yl)morpholin-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-3- methylphenyl)-3-methylpiperidine-2, 6-dione B142. 1H NMR (400 MHz, DMSO-d6) δ 10 .87 (s, 1H), 9.04 (d, J= 10.0 Hz, 1H), 8.14 (s, 1H), 7.79-7.65 (m, 1H), 7.65-7.52 (m, 2H), 7.47 (t, J = 6.8 Hz, 1H), 7.45-7.34 (m, 1H), 7.32-7.20 (m, 2H), 7.11-7.02 (m, 2H), 5.72-5.57 (m, 1H), 4.91- 4.56 (m, 1H), 4.32 (dd, J = 14.0, 17.2 Hz, 1H), 4.15-3.97 (m, 2H), 3.86-3.64 (m, 2H), 3.63-3.50 (m, 1H), 3.20-3.07 (m, 2H), 2.91-2.82 (m, 1H), 2.76-2.65 (m, 1H), 2.59 (s, 3H), 2.54 (s, 1H), 2.47-2.39 (m, 2H), 2.33 (d, J= 9.2 Hz, 4H), 2.28-2.13 (m, 2H), 2.11-2.05 (m, 2H), 2.05-1.94 (m, 2H), 1.81-1.64 (m, 2H), 1.61 (dd, J = 12, 10.4 Hz, 3H), 1.40 (m, 1H), 1.40 (d, J= 2.0 Hz, 3H); MS (ESI) m/r 756.5 [M+H]+.
Figure imgf000232_0002
[00482] (37?)-3-(4-(8-(5-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B143. 1H NMR (400 MHz, DMSO-d6) δ 10 .85 (s, 1H), 9.44 (s, 1H), 8.92 (s, 1H), 8.71 (d, J= 6.8 Hz, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 8.00 (d, J= 6.8 Hz, 1H), 7.62 (t, J= 6.4 Hz, 1H), 7.50-7.44 (m, 1H), 7.43-7.36 (m, 1H), 7.27-7.20 (m, 2H), 7.15 (d, J = 31.2 Hz, 1H), 7.05-6.99 (m, 2H), 5.71 (t, J= 6.8 Hz, 1H), 3.62 (s, 2H), 3.29-3.28 (m, 1H), 3.27-3.26 (m, 1H), 3.26-3.24 (m, 1H), 2.75 (s, 3H), 2.42 (d, J= 13.2 Hz, 2H), 2.34 (s, 3H), 2.32- 2.27 (m, 2H), 2.21-2.12 (m, 2H), 2.08-1.98 (m, 2H), 1.62 (d, J= 7.2 Hz, 3H), 1.59 (s, 2H), 1.39 (s, 3H), 1.25 (q, J= 11.2 Hz, 2H); MS (ESI) m/r 765.3 [M+H]+.
Figure imgf000233_0001
[00483 ] (R)-3 -(4-( 1 -((5 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethy l)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)pyridin-3-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B144. 1H NMR (400 MHz, DMSO-d6) 6 10.85 (s, 1H), 9.54 (s, 1H), 9.42 (d, .7= 1.2 Hz, 1H), 9.05 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.16 (s, 1H), 8.00 (d, J= 6.8 Hz, 1H), 7.66 (t, J= 7.6 Hz, 1H), 7.48 (t, J= 7.2 Hz, 1H), 7.41-7.10 (m, 3H), 7.06-7.00 (m, 2H), 5.73 (t, J= 6.8 Hz, 1H), 3.70 (s, 2H), 2.99 (d, J= 11.2 Hz, 2H), 2.76 (s, 3H), 2.72-2.64 (m, 1H), 2.42- 2.31 (m, 2H), 2.29 (s, 3H), 2.21-2.10 (m, 2H), 2.09-1.96 (m, 2H), 1.67 (d, J= 6.8 Hz, 7H), 1.39 (s, 3H); MS (ESI) m/z: 722.2 [M+H]+.
Figure imgf000233_0002
[00484] (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3- methylpiperidine-2, 6-dione B145. 1H NMR (400 MHz, DMSO-d6) δ 10 .98 (s, 1H), 9.49 (s, 1H), 8.91 (s, 1H), 8.38 (br d, J= 7.2 Hz, 1H), 8.32-8.23 (m, 1H), 8.00 (br d, J= 6.8 Hz, 1H), 7.73- 7.59 (m, 2H), 7.55 (br d, J= 8.4 Hz, 1H), 7.52-7.42 (m, 3H), 7.40-7.09 (m, 2H), 5.72 (quin, J = 6.8 Hz, 1H), 3.70 (s, 2H), 3.04 (br d, J= 10.4 Hz, 2H), 2.85-2.70 (m, 4H), 2.56-2.51 (m, 1H), 2.42 (br dd, J= 4.3, 9.2 Hz, 1H), 2.21-2.02 (m, 4H), 1.81 (q, J= 11.4 Hz, 2H), 1.72-1.62 (m, 5H), 1.46 (s, 3H); MS (ESI) m/z: 793.3 [M+H]+.
Figure imgf000234_0001
[00485] (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-(trifIuoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione B146. 1H NMR (400 MHz, DMSO-76) 6 10.98 (s, 1H), 9.50 (s, 1H), 8.92 (s, 1H), 8.27 (s, 1H), 8.22 (br d, J= 7.6 Hz, 1H), 8.02 (br d, J= 6.4 Hz, 1H), 7.73-7.62 (m, 2H), 7.61-7.54 (m, 2H), 7.54-7.44 (m, 3H), 7.41-7.09 (m, 2H), 5.73 (br t, J= 6.4 Hz, 1H), 3.66 (s, 2H), 3.02 (br d, J= 11.2 Hz, 2H), 2.87-2.69 (m, 4H), 2.56-2.51 (m, 1H), 2.43 (br d, J= 9.2 Hz, 1H), 2.18-2.02 (m, 4H), 1.90-1.74 (m, 2H), 1.67 (br d, J= 7.2 Hz, 5H), 1.47 (s, 3H); MS (ESI) m z.' 775.3 [M+H]+.
Figure imgf000234_0002
[00486] (R) - 3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3-methyl- piperidine-2, 6-dione B147. 1H NMR (400 MHz, DMSO-7e) δ 10 .90 (s, 1H), 9.51 (s, 1H), 8.93 (s, 1H), 8.27 (s, 1H), 8.23 (br d, J= 7.6 Hz, 1H), 8.03 (d, J= 6.8 Hz, 1H), 7.66 (br t, J= 7.2 Hz, 1H), 7.62-7.57 (m, 1H), 7.54-7.46 (m, 2H), 7.40-7.13 (m, 2H), 6.93-6.86 (m, 2H), 5.78-5.68 (m, 1H), 3.65 (s, 2H), 2.99 (br d, 7 = 7.6 Hz, 2H), 2.81-2.72 (m, 4H), 2.45 (br d, J - 3.6 Hz, 1H), 2.42-2.35 (m, 1H), 2.33 (s, 3H), 2.13-2.00 (m, 6H), 1.67 (d, J= 7.2 Hz, 3H), 1.61 (br d, 7= 10.4 Hz, 2H), 1.41 (s, 3H); MS (ESI) m z. 739.3 [M+H]+.
Figure imgf000235_0001
[00487] (R)-3-(4-(1-(5-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione B148. 1H NMR (400 MHz, DMSO-d6) δ 10 .90 (s, 1H), 9.51 (s, 1H), 8.92 (s, 1H), 8.39 (dd, J= 2.4, 7.2 Hz, 1H), 8.32-8.22 (m, 1H), 8.01 (d, J= 6.8 Hz, 1H), 7.66 (br t, J= 7.2 Hz, 1H), 7.52-7.43 (m, 2H), 7.40-7.12 (m, 2H), 6.91-6.84 (m, 2H), 5.73 (quin, 7= 6.8 Hz, 1H), 3.69 (s, 2H), 3.00 (br d, 7= 10.4 Hz, 2H), 2.75 (s, 4H), 2.45 (br d, 7= 4.0 Hz, 1H), 2.38-2.33 (m, 1H), 2.32 (s, 3H), 2.17-2.00 (m, 6H), 1.67 (d, 7= 7.2 Hz, 3H), 1.62 (br d, 7= 11.6 Hz, 2H), 1.41 (s, 3H); MS (ESI) m/z 739.3 [M+H]+.
Figure imgf000235_0002
[00488] (R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)thiophen-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B149. 1 H NMR (400 MHz, DMSO-d6) δ 10 .87 (s, 1H), 9.39 (d, J = 1.0 Hz, 1H), 8.73 (d, 7= 0.9 Hz, 1H), 8.26 (d, 7= 1.4 Hz, 1H), 7.86 (d, 7= 7.0 Hz, 1H), 7.80 (d, 7= 1.4 Hz, 1H), 7.63 (t, 7= 7.5 Hz, 1H), 7.48 (t, 7= 7.0 Hz, 1H), 7.28-7.21 (m, 2H), 7.08-7.02 (m, 2H), 5.71 (p, 7= 7.1 Hz, 1H), 3.81 (s, 2H), 3.33 (s, 2H), 3.05 (s, 1H), 2.82-2.58 (m, 4H), 2.49-2.40 (m, 1H), 2.38-2.25 (m, 4H), 2.17 (t, 7= 11.0 Hz, 2H), 2.12-1.99 (m, 2H), 1.74-1.58 (m, 7H), 1.40 (s, 3H); MS (ESI) m/z: 727.3 [M+H]+.
Figure imgf000236_0001
[00489] (R)-3 -(4-( 1 -(5-( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3-methyl- piperidine-2, 6-dione B150. 1H NMR (400 MHz, DMSO-d6) 3 9.42 (s, 1H), 8.76 (s, 1H), 8.37 (dd, 7= 2.0, 7.2 Hz, 1H), 8.29-8.22 (m, 1H), 7.61 (t, J= 7.2 Hz, 1H), 7.43 (t, J= 6.8 Hz, 1H), 7.33-7.24 (m, 2H), 7.17 (t, J= 7.6 Hz, 1H), 7.14-6.82 (m, 3H), 5.74 (q, J= 6.8 Hz, 1H), 3.74 (s, 2H), 3.12 (d, J= 1 1.6 Hz, 2H), 2.90-2.80 (m, 1H), 2.76 (s, 3H), 2.55-2.47 ( ,, 1H), 2.44-2.37 (m, 1H), 2.34-2.24 (m, 2H), 2.22-2.09 (m, 2H), 1.90-1.77 (m, 4H), 1.72 (d, J= 7.2 Hz, 3H), 1.49 (s, 3H); MS (ESI) m/z: 743.1 [M+H]+.
Figure imgf000236_0002
[00490] (R) - 3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluorophenyl)-3-methylpiperidine- 2,6-dione B151. 1H NMR (400 MHz, DMSO-d6) δ 10 .92 (s, 1H), 9.50 (s, 1H), 8.92 (s, 1H), 8.27 (s, 1H), 8.22 (d, J= 7.8 Hz, 1H), 8.01 (d, J= 6.8 Hz, 1H), 7.65 (t, J= 7.6 Hz, 1H), 7.61-7.55 (m, 1H), 7.53-7.43 (m, 2H), 7.42-7.35 (m, 1H), 7.34-7.07 (m, 3H), 7.03 (dd, J= 1.6, 8.0 Hz, 1H), 5.73 (t, J= 6.8 Hz, 1H), 3.65 (s, 2H), 2.99 (d, J= 11.2 Hz, 2H), 2.84-2.76 (tn, 1H), 2.74 (s, 3H), 2.46-2.31 (m, 2H), 2.18-2.02 (m, 4H), 1.73 (d, 7= 2.4 Hz, 4H), 1.66 (d, 7= 7.2 Hz, 3H), 1.42 (s, 3H); MS (ESI) m/z: 1252 [M+H]+.
Figure imgf000237_0001
[00491] (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)arnino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzoyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B152. 1H NMR (400 MHz, DMSO-d6) δ 10 .90 (s, 1H), 9.50 (s, 1H), 8.97 (s, 1H), 8.51-8.44 (m, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 8.03 (d, J= 6.4 Hz, 1H), 7.65 (t, J= 7.2 Hz, 1H), 7.58 (t, J= 8.8 Hz, 1H), 7.49 (t, J= 6.8 Hz, 1H), 7.36-7.10 (m, 6H), 5.73 (quin, J= 6.8 Hz, 1H),
4.75 (d, J= 12.8 Hz, 1H), 3.61 (d, J= 12.8 Hz, 1H), 3.29-3.20 (m, 1H), 3.02-2.81 (m, 2H), 2.75
(s, 3H), 2.45 (d, J= 15.2 Hz, 1H), 2.39-2.25 (m, 1H), 2.16-1.90 (m, 3H), 1.82 (d, J= 8.4 Hz, 1H), 1.68 (d, J= 7.2 Hz, 3H), 1.65 (s, 2H), 1.42 (s, 3H); MS (ESI) m/z: 739.2 [M+H]+.
Figure imgf000237_0002
[00492] ((R) -3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- 2,6-dioxopiperidin-l-yl)methyl pivalate B153. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.91 (s, 1H), 8.38 (dd, J= 2.4, 7.2 Hz, 1H), 8.30-8.25 (m, 1H), 8.00 (d, J= 6.8 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.49-7.38 (m, 2H), 7.29-7.09 (m, 3H), 7.06-6.97 (m, 2H), 5.78-5.69 (m, 2H), 5.65 (d, J = 9.2 Hz, 1H), 3.69 (s, 2H), 3.01 (d, J= 10.8 Hz, 2H), 2.74 (s, 3H), 2.68-2.60 (m, 2H), 2.41-2.30 (m, 2H), 2.27 (s, 3H), 2.22-2.11 (m, 4H), 1.66 (d, J= 7.2 Hz, 6H), 1.43 (s, 3H), 1.11 (s, 9H); MS (ESI) m/z: 853.3 [M+H]+.
Figure imgf000238_0001
[00493 ] 3-(4-(1-(3-(l -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione B154.
H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.50 (s, 1H), 8.93 (s, 1H), 8.28 (s, 1H), 8.22 (br d, .7= 8.0 Hz, 1H), 8.02 (br d, J = 6.4 Hz, 1H), 7.65 (br t, J= 7.2 Hz, 1H), 7.61-7.54 (m, 1H), 7.54-7.43 (m, 2H), 7.41-7.08 (m, 3H), 7.02-6.93 (m, 2H), 5.80-5.65 (m, 1H), 3.74 (br dd, J= 4.8, 11.2 Hz, 1H), 3.66 (s, 2H), 3.01 (br d, J= 10.8 Hz, 2H), 2.77-2.58 (m, 5H), 2.45 (br d, J= 4.4 Hz, 1H), 2.28 (s, 3H), 2.20-2.07 (m, 3H), 2.05-1.95 (m, 1H), 1.67 (br d, J= 7.2 Hz, 7H); MS (ESI) m/z: 707.3 [M+H]+.
Figure imgf000238_0002
[00494] (R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)pyridin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B155. 1H NMR (400 MHz, DMSO-d6) δ 10 .86 (s, 1H), 9.57 (s, 1H), 9.09 (s, 1H), 8.76 (d, J= 5.2 Hz, 1H), 8.33 (s, 1H), 8.16 (s, 1H), 8.14 (dd, J= 1.6, 5.2 Hz, 1H), 8.09 (d, ,7= 6.8 Hz, 1H), 7.66 (t, .7= 7.2 Hz, 1H), 7.52-7.44 (m, 1H), 7.39-7.11 (m, 3H), 7.07- 7.00 (m, 2H), 5.73 (q, J= 6.8 Hz, 1H), 3.78 (s, 2H), 3.03 (d, J= 11.2 Hz, 2H), 2.77 (s, 3H), 2.73- 2.65 (m, 1H), 2.45-2.40 (m, 1H), 2.37-2.31 (m, 1H), 2.29 (s, 3H), 2.27-2.17 (m, 2H), 2.10-1.97 (m, 2H), 1.73-1.70 (m, 2H), 1.68 (s, 3H), 1.67 (s, 2H), 1.39 (s, 3H); MS (ESI) m'z. 1212 [M+H]+.
Figure imgf000239_0002
[00495 ] (R)-3 -(3 -Chloro-4-( 1 -(5-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B156. 1H NMR (400 MHz, DMSO-d6) 3 1.42 (s, 3H), 1.66 (d, J =7.2 Hz, 4H), 1.70 (s, 3H), 2.06 (d, J= 10.8 Hz, 2H), 2.20 (t, J= 10.8 Hz, 2H), 2.37 (d, J= 8.4 Hz, 1H), 2.46 (s, 1H), 2.74 (s, 3H), 2.83-2.95 (m, 1H), 3.03 (d, J= 10.4 Hz, 2H), 3.60-3.79 (m, 2H), 5.72 (quin, J= 6.8 Hz, 1H), 7.10-7.28 (m, 3H), 7.28-7.33 (m, 1H), 7.37-7.41 (m, 1H), 7.41-7.51 (m, 2H), 7.64 (t, J= 7.2 Hz, 1H), 7.99 (d, J= 6.8 Hz, 1H), 8.14 (s, 1H), 8.27 (d, J= 5.2 Hz, 1H), 8.38 (d, J= 6.8 Hz, 1H), 8.91 (s, 1H), 9.42-9.54 (m, 1H), 10.94 (s, 1H); MS (ESI) m/z: 759.2 [M+H]+.
Figure imgf000239_0001
[00496] (R)-3-(3-Chloro-4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-4-methylpyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B157. 1 NHMR (400 MHz, DMSO-d6) 3 1.43 (s, 3H), 1.66 (d, J= 6.8 Hz, 4H), 1.70- 1.80 (m, 3H), 2.02-2.10 (m, 2H), 2.10-2.19 (m, 2H), 2.31-2.41 (m, 1H), 2.46 (s, 1H), 2.66-2.79 (m, 3H), 2.91 (t, J= 10.8 Hz, 1H), 2.97-3.07 (m, 2H), 3.66 (s, 2H), 5.62-5.85 (m, 1H), 7.09-7.29 (m, 3H), 7.32 (s, 1H), 7.37-7.45 (m, 1H), 7.45-7.53 (m, 2H), 7.55-7.61 (m, 1H), 7.65 (t, J= 7.2 Hz, 1H), 7.99-8.04 (m, 1H), 8.15 (s, 1H), 8.22 (d, J= 7.6 Hz, 1H), 8.27 (s, 1H), 8.92 (s, 1H), 9.50 (s, 1H), 10.94 (s, 1H); MS (ESI) m/z: 741.2 [M+H]+.
Figure imgf000240_0001
[00497] (R)-3 -(3 -Cyclopropyl-4-(l -(5-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione B158. 1H NMR (400 MHz, DMSO-d6) 6 10.86 (s, 1H), 9.50 (s, 1H), 8.91 (s, 1H), 8.39 (d, J= 7.6 Hz, 1H), 8.27 (dd, J= 2.4, 3.2 Hz, 1H), 8.00 (d, J= 6.4 Hz, 1H), 7.64 (t, J= 6.8 Hz, 1H), 7.52-7.36 (m, 2H), 7.29-6.97 (m, 4H), 6.84 (s, 1H), 5.72 (t, J= 6.8 Hz, 1H), 3.70 (s, 2H), 3.14-2.96 (m, 3H), 2.74 (s, 3H), 2.44 (s, 1H), 2.36-2.30 (m, 1H), 2.26-2.14 (m, 2H), 2.09-1.92 (m, 3H), 1.78-1.63 (m, 7H), 1.38 (s, 3H), 0.91 (d, J= 8.0 Hz, 2H), 0.55 (d, J= 5.2 Hz, 2H); MS (ESI) m/z: 765.2 [M+H]+.
Figure imgf000240_0002
[00498] (R)-3 -(3 -Cyclopropyl-4-( 1 -(3-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B159. 1H NMR (400 MHz, DMSO-d6) δ 10 .86 (s, 1H), 9.08 (s, 1H), 8.91 (d, J= 6.4 Hz, 1H), 8.85 (s, 1H), 8.17 (s, 1H), 8.10 (d, 7= 7.6 Hz, 1H), 7.72 (t, J= 7.2 Hz, 1H), 7.56-7.48 (m, 2H), 7.43 (d, ,/= 7.2 Hz, 1H), 7.40-7.09 (m, 3H), 7.04 (d, J= 8.4 Hz, 1H), 6.84 (s, 1H), 5.82 (t, J = 7.2 Hz, 1H), 3.63 (s, 2H), 3.16-2.95 (m, 3H), 2.42 (s, 4H), 2.32 (s, 1H), 2.13 (t, J= 9.2 Hz, 2H), 2.07-1.94 (m, 3H), 1.77-1.61 (m, 7H), 1.38 (s, 3H), 0.90 (d, J= 8.4 Hz, 2H), 0.55 (d, J= 5.2 Hz, 2H); MS (ESI) m/z: 747.1 [M+H]+.
Figure imgf000241_0001
[00499] (R)-3 -(4-( 1 -(((5)- 1 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-
4-methylpyrido[3,4-d]pyridazin-7-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B160. 1H NMR (400 MHz, DMSO-d6) δ 10 .86 (s, 1H), 8.99 (s, 1H), 7.59-7.39 (m, 4H), 7.39-6.99 (m, 5H), 5.61 (t, J= 6.4 Hz, 1H), 4.59-4.39 (m, 1H),
4.25-4.01 (m, 1H), 3.64-3.36 (m, 4H), 3.08-2.95 (m, 2H), 2.60 (s, 2H), 2.54 (s, 3H), 2.29 (s, 4H),
2.26-2.17 (m, 3H), 2.08-1.97 (m, 3H), 1.90-1.78 (m, 2H), 1.76-1.64 (m, 4H), 1.59 (d, J= 7.2 Hz, 3H), 1.39 (s, 3H); MS (ESI) m/r. 746.4 [M+H]+.
Figure imgf000241_0002
[00500] (R)-3-(4-(1-(5-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methylpiperidine-2, 6-dione B161. 1H NMR (400 MHz, DMSO-d6) δ 10 .94 (s, 1H), 9.50 (s, 1H), 8.91 (s, 1H), 8.38 (m, 1H), 8.23-8.31 (m, 1H), 7.99 (d, J= 6.8 Hz, 1H), 7.65 (t, J= 7.2 Hz, 1H), 7.42-7.50 (m, 2H), 7.09-7.40 (m, 2H), 6.97 (d, J= 10.4 Hz, 2H), 5.72 (m, 1H), 3.68 (s, 2H), 3.00 (d, J= 10.8 Hz, 2H), 2.85-2.95 (m, 1H), 2.74 (s, 3H), 2.45-2.48 (m, 1H), 2.38 (m, 1H), 2.10-2.21 (m, 3H), 1.90-2.08 (m, 3H), 1.66 (d, 7.2 Hz, 5H), 1.43 (s, 3H); MS
Figure imgf000241_0003
761.3 [M+H]+.
Figure imgf000242_0001
[00501] (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-2-methylphenyl)-3-methyl- piperidine-2, 6-dione B162. 1H NMR (400 MHz, DMSO-d6) δ 10 .89 (s, 1H), 9.50 (s, 1H), 8.92 (s, 1H), 8.27 (s, 1H), 8.25-8.11 (m, 2H), 8.02 (d, J= 6.8 Hz, 1H), 7.65 (t, J= 7.6 Hz, 1H), 7.61- 7.55 (m, 1H), 7.53-7.43 (m, 2H), 7.24 (d, J= 4.8 Hz, 1H), 7.19-7.10 (m, 2H), 5.73 (q, J= 6.8 Hz, 1H), 3.66 (s, 3H), 3.00 (d, J= 10.4 Hz, 3H), 2.84-2.76 (m, 2H), 2.74 (s, 3H), 2.39-2.19 (m, 2H), 2.19-2.09 (m, 2H), 2.02 (d, J= 2.8 Hz, 3H), 1.73 (s, 4H), 1.68-1.62 (m, 6H); MS (ESI) m/z: 739.3 [M+H]+.
Figure imgf000242_0002
[00502] (R)-3 -(3 -(Difluoromethyl)-4-( 1 -(5 -( 1 -((( (R)- 1 -(3 -(difluoromethy l)-2-fluoro- phenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3-methylpiperidine-2, 6-dione B163. NVIR (400 MHz, DMSO-d6) δ 10 .94 (s, 1H), 9.49 (s, 1H), 8.90 (s, 1H), 8.41-8.34 (m, 1H), 8.31-8.24 (m, 1H), 7.99 (br d, J= 6.8 Hz, 1H), 7.64 (br t, J= 7.2 Hz, 1H), 7.54-7.39 (m, 5H), 7.39-7.10 (m, 3H), 5.72 (quin, J= 6.8 Hz, 1H), 3.69 (s, 2H), 3.01 (br d, J- 10.8 Hz, 2H), 2.89-2.82 (m, 1H), 2.75-2.72 (m, 3H), 2.48-2.43 (m, 1H), 2.41-2.31 (m, 1H), 2.21-2.12 (m, 2H), 2.11-2.00 (m, 2H), 1.82-1.72 (m, 2H), 1.66 (br d, J= 7.2 Hz, 5H), 1.43 (s, 3H); MS (ESI) m z'. 1152 [M+H]+.
Figure imgf000243_0001
[00503] (R)-3 -(3 -(Difluoromethyl)-4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoro- phenyl)ethyl)amino)-4-methylpyrido[3,4-7]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione B164. 1H NMR (400 MHz, DMSO-7e) δ 10 .95 (s, 1H), 9.50 (s, 1H), 8.92 (s, 1H), 8.27 (s, 1H), 8.22 (d, 7= 7.6 Hz, 1H), 8.01 (d, 7= 6.8 Hz, 1H), 7.65 (br t, 7= 7.6 Hz, 1H), 7.61-7.55 (m, 1H), 7.55-7.41 (m, 5H), 7.39-7.10 (m, 3H), 5.73 (quin, 7= 6.8 Hz, 1H), 3.66 (s, 2H), 2.99 (br d, 7= 10.8 Hz, 2H), 2.91-2.85 (m, 1H), 2.74 (s, 3H), 2.46 (br d, 7= 2.8 Hz, 1H), 2.41-2.27 (m, 1H), 2.16-2.01 (m, 4H), 1.82-1.71 (m, 2H), 1.66 (br d, 7= 7.2 Hz, 5H), 1.44 (s, 3H); MS (ESI) m/z 7:57.2 [M+H]+.
Figure imgf000243_0002
[00504] (R)-3 -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-7]pyridazin-7-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione B165. 1H NMR (400 MHz, DMSO-d6) δ 10 .95 (s, 1H), 9.50 (s, 1H), 8.92 (s, 1H), 8.26 (s, 1H), 8.22 (d, J= 7.6 Hz, 1H), 8.01 (d, 7 = 6.8 Hz, 1H), 7.65 (t, 7 = 7.2 Hz, 1H), 7.61-7.55 (m, 1H), 7.53-7.44 (m, 2H), 7.39 (s, 2H), 6.98 (d, J= 10.4 Hz, 2H), 5.73 (quin, 7 = 6.8 Hz, 1H), 3.64 (s, 2H), 2.98 (br d, J= 10.4 Hz, 2H), 2.95-2.86 (m, 1H), 2.74 (s, 3H), 2.48-2.44 (m, 1H), 2.39 (td, 7= 4.4, 13.2 Hz, 1H), 2.22-1.95 (m, 6H), 1.67 (d, 7= 7.2 Hz, 5H), 1.44 (s, 3H); MS (ESI) m/z: 743.4 [M+H]+.
Figure imgf000244_0002
[00505] 3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(Difluoromethyl )-2-fluorophenyI )ethyl )ami no)-4-m ethyl - pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- dione B166. 1H NMR (400 MHz, DMSO-d6) δ 10 .82 (s, 1H), 9.51 (s, 1H), 8.92 (s, 1H), 8.27 (s, 1H), 8.22 (d, J= 7.6 Hz, 1H), 8.02 (d, J= 7.2 Hz, 1H), 7.65 (t, J= 7.6 Hz, 1H), 7.61-7.56 (m, 1H), 7.53-7.45 (m, 2H), 7.41-7.08 (m, 2H), 6.89-6.80 (m, 2H), 5.73 (t, J= 6.8 Hz, 1H), 3.82-3.72
(m, 1H), 3.65 (s, 2H), 3.03-2.94 (m, 2H), 2.84-2.70 (m, 4H), 2.69-2.59 (m, 1H), 2.32 (s, 3H), 2.27-1.92 (m, 7H), 1.67 (d, J= 6.8 Hz, 3H), 1.63-1.55 (m, 2H); MS (ESI) m/r. 725.5 [M+H]+.
Figure imgf000244_0001
[00506] 3-(4-(1-(5-(1-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine- 2,6-dione B167. 1H NMR (400 MHz, DMSO-d6) δ 10 .81 (s, 1H), 9.50 (s, 1H), 8.91 (s, 1H), 8.39 (dd, .7= 2.4, 7.2 Hz, 1H), 8.31-8.23 (m, 1H), 8.15 (s, 1H), 7.99 (d, J= 6.8 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.52-7.42 (m, 2H), 7.39-7.11 (m, 2H), 6.88-6.79 (m, 2H), 5.72 (t, .7= 6.8 Hz, 1H), 3.77 (dd, .7= 4.8, 11.6 Hz, 1H), 3.69 (s, 2H), 3.01 (d, .7= 10.4 Hz, 2H), 2.82-2.75 (m, 1H), 2.74 (s, 3H), 2.68-2.60 (m, 1H), 2.46 (s, 1H), 2.31 (s, 3H), 2.22-2.11 (m, 3H), 2.09-1.92 (m, 3H), 1.67 (d, J= 6.8 Hz, 3H), 1.62 (d, J= 11.2 Hz, 2H); MS (ESI) m/z: 743.0 [M+H]+.
Figure imgf000245_0001
[00507] (R)-3 -(4-( 1 -((6-(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethy l)amino)- 1 - methylphthal azin-6-yl)pyri din-2 -yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C001. 1H NMR (400 MHz, DMSO-d6) δ 10 .93-10.78 (m, 1H), 9.09 (s, 1H), 8.71-8.61 (m, 1H), 8.20 (d, J= 7.6 Hz, 1H), 8.11 (d, J= 8.4 Hz, 1H), 8.04 (t, J= 7.6 Hz, 1H), 7.82 (br d, J = 6.8 Hz, 1H), 7.65 (br t, J= 7.6 Hz, 1H), 7.58 (d, J= 7.6 Hz, 1H), 7.47 (br t, J= 7.2 Hz, 1H), 7.41-7.09 (m, 3H), 7.08-6.99 (m, 2H), 5.75 (quin, J= 6.8 Hz, 1H), 3.80 (s, 2H), 3.08-2.99 (m, 2H), 2.72-2.64 (m, 4H), 2.46-2.40 (m, 2H), 2.36-2.31 (m, 1H), 2.29 (s, 3H), 2.25 (br d, J= 9.6 Hz, 2H), 2.04 (br s, 1H), 1.76-1.61 (m, 7H), 1.40 (s, 3H); MS (ESI) m/z: 721.4 [M+H]+.
Figure imgf000245_0002
[00508] (R)-3 -(4-( 1 -((2-(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluoropheny l)ethyl)amino)- 1 - methylphthal azin-6-yl)pyri din-4-yl )methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C002. 1H NMR (400 MHz, DMSO-d6) δ 10 .86 (s, 1H), 9.13 (s, 1H), 8.75 (d, J= 4.8 Hz, 1H), 8.60 (dd, J= 1.2, 8.6 Hz, 1H), 8.17-8.07 (m, 2H), 7.90 (d, J= 7.2 Hz, 1H), 7.67 (br t, J = 7.2 Hz, 1H), 7.52-7.42 (m, 2H), 7.39-7.12 (m, 3H), 7.07-7.02 (m, 2H), 5.79-5.70 (m, 1H), 3.71 (s, 2H), 2.99 (br d, J= 10.8 Hz, 2H), 2.67 (s, 3H), 2.43 (br dd, J= 3.6, 13.4 Hz, 2H), 2.35-2.31 (m, 1H), 2.29 (s, 3H), 2.23-2.16 (m, 2H), 2.09-2.00 (m, 2H), 1.70 (br s, 4H), 1.65 (d, J= 7.6 Hz, 3H), 1.40 (s, 3H); MS (ESI) m/z: 721.6 [M+H]+.
Figure imgf000246_0001
[00509] (R)-3 -(4-( 1 -((4-(4-(((R)- 1 -(3 -(Difluoromethyl)-2-fluorophenyl)ethy l)amino)- 1 - methylphthal azin-6-yl)pyri din-2 -yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C003. 1H NMR (400 MHz, DMSO-d6) δ 10 .86 (s, 1 H), 8.92 (s, 1 H), 8.72 (d, J= 5.0 Hz, 1 H), 8.31 (d, J= 8.4 Hz, 1 H), 8.11-8.19 (m, 1 H), 7.94 (s, 1 H), 7.86 (d, J= 6.2 Hz, 2 H), 7.66 (t, J= 7 A Hz, 1 H), 7.47 (t, J= 6.4 Hz, 1 H), 7.10-7.41 (m, 3 H), 6.98-7.07 (m, 2 H), 5.76 (t, J= 6.8 Hz, 1 H), 3.78-3.82 (m, 2 H), 3.04 (d, J= 10.2 Hz, 2 H), 2.68 (s, 3 H), 2.31-2.47 (m, 2 H), 2.30 (s, 3 H), 2.18-2.27 (m, 2 H), 1.98-2.12 (m, 2 H), 1.53-1.79 (m, 7 H), 1.40 (s, 3 H); MS (ESI) m/z: 721.3 [M+H]+.
Figure imgf000246_0002
[00510] K562 cells were cultured in IMDM media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. The cells were plated in 384-well plates at 500 cells/well. The cells were incubated overnight and then treated with DMSO (control) or a compound for 3 days at 37 °C under 5% CO2. A CELLTITER-GLO® reagent (100 pL) was then added to each well. After a 10 min incubation with shaking, luminescence was measured using a PERKINELMER ENVISION® multimode plate reader. The results are summarized in Table 1, where “A” represents an IC50 of no greater than 50 nM, “B” represents an IC50 of greater than 50 nM and no greater than 200 nM; “C” represents an IC50 of greater than 200 nM and no greater than 1 pM; and “D” represents an IC50 of greater than 1 pM.
TABEL 1. Inhibition of Cancerous C6lls
Figure imgf000247_0001
Figure imgf000248_0001
Example B2
SOSl-HiBiT Degradation Assay
[00511] H358 cells were engineered to express a HiBiT-tagged endogenous S0S1 protein.
The cells were cultured in RPMI 1640 media supplemented with 10% fetal bovine serum, streptomycin, and penicillin. The cells were seeded in a white walled 384-well plate at 5,000 cells/well in 50 pL culture media. The cells were incubated at 37 °C under 5% CO2 overnight. The cells were then treated with DMSO (control) or a compound for 6 h at 37 °C under 5% CO2. After incubation, 25 pL media was removed from each cell and 25 pL NANO-GLO® lytic detection reagent was added to each well. After a 10 min incubation with shaking, luminescence was measured using a CALRIOSTAR PLUS microplate reader.
[00512] The results are summarized in Table 2, where “A” represents a DC50 of no greater than 50 nM, “B” represents a DC50 of greater than 50 nM and no greater than 200 nM; “C” represents a DC50 of greater than 200 nM and no greater than 1 pM; and “D” represents a DC50 of greater than 1 pM; and where “A'” represents a Dmax of no less than 70%, “B'” represents a
Dmax of less than 70% and no less than 50%; “C'” represents a Dmax of less than 50% and no less than 30%; and “D'” represents a Dmax of less than 30%.
TAB EL 2. Effect on S0S1 Protein Degradation
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
[00513] The examples set forth above are provided to give those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments and are not intended to limit the scope of what is disclosed herein. Modifications that are obvious to persons of skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference.

Claims

What is claimed is:
1. A compound of Formula (I):
Figure imgf000252_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
A is C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
L is C1-6 alkylene, C7-15 aralkylene, or a linker;
U and V are each independently -C(R4a)= or -N=;
X is -N= or -C(R4b)=;
R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R3 is C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1 bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1 d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c;
R2a and R2b are each independently hydrogen, deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, heteroaryl, or heterocyclyl; each R4a and R4b is independently hydrogen or R4;
Re is an E3 ubiquitin ligase binding moiety; each R1a, Rlb, R1c, and R1d is independently hydrogen, deuterium, C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; and a is an integer of 0, 1, or 2; wherein each alkyl, alkylene, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORb)ORc, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRe, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen or deuterium; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qa is independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NR‘Rg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OP(O)(ORf)ORg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, NReC(O)Rh, NReC(O)ORf, NReC(O)NRfRg, NReC(O)SRf, NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rb, -NReS(O)2Rb, -NReS(O)NRfR8, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, R1, Rg, and Rh is independently (i) hydrogen or deuterium; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rf and Rg together with the N atom to which they are attached form heterocyclyl.
2. The compound of claim 1, wherein A is C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q.
3. The compound of claim 1 or 2, wherein A is phendiyl, monocyclic heteroarylene, or monocyclic heterocyclylene, each optionally substituted with one or more substituents Q.
4. The compound of any one of claims 1 to 3, wherein A is phendiyl, furandiyl, thiendiyl, pyridindiyl, 1,2-dihydropyridindiyl, piperidindiyl, morpholindiyl, or piperazindiyl, each optionally substituted with one or more substituents Q.
5. The compound of any one of claims 1 to 4, wherein A is phen-l,3-diyl, furan-2,4- diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin-3,5-diyl, l,2-dihydropyridin-3,5- diyl, l,2-dihydropyridin-l,5-diyl, morpholin-2,4-diyl, piperazin- 1,4-diyl, or piperidin- 1 ,3-diyl, each optionally substituted with one or more substituents Q.
6. The compound of any one of claims 1 to 5, wherein A is phen-l,3-diyl, 2- fluorophen- 1,3 -diyl, 4-fluorophen- 1,3 -diyl, 5 -fluorophen- 1,3 -diyl, 2-chlorophen-l,3-diyl, 4- chlorophen-l,3-diyl, 5-chlorophen-l,3-diyl, 2-methylphen-l,3-diyl, 4-methylphen-l,3-diyl, 5- m ethylphen- 1,3 -diyl, furan-2,4-diyl, thien-2,4-diyl, pyridin-2,4-diyl, pyridin-2,6-diyl, pyridin- 3,5-diyl, l-methyl-2-oxo-l,2-dihydropyridin-3,5-diyl, 2-oxo-l,2-dihydropyridin-l,5-diyl, 3- fluoropiperidin-l,3-diyl, morpholin-2,4-diyl, or piperazin- 1,4-diyl.
7. The compound of any one of claims 1 to 6, wherein R3 is C6-14 aryl or heteroaryl, each optionally substituted with one or more substituents Q.
8. The compound of any one of claims 1 to 7, wherein R3 is phenyl or monocyclic heteroaryl, each optionally substituted with one or more substituents Q.
9. The compound of any one of claims 1 to 8, wherein R2b is hydrogen.
10. The compound of any one of claims 1 to 9, wherein X is -C(R4b)=.
1 1 . The compound of any one of claims 1 to 9, wherein X is -N=.
12. The compound of claim 10, wherein U is -C(R4a)=; and V is -N=.
13. The compound of claim 10, wherein U is -N=; and V is -C(R4a)=.
14. The compound of any one of claims 1 to 3, having the structure of Formula (VI):
Figure imgf000255_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
U5, V5, X5, and Z5 are each independently -C(R5)= or -N=; and each R3a, R3b, R3c, R3d, R3e, and R5 is each independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1 a)NR1bR1c,
C(S)R1a, C(S)OR1a, C(S)NR1bR1c, OR1a, OC(O)R1a, OC(O)OR1a, OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c.
15. The compound of any one of claims 1 to 3, having the structure of Formula (VII):
Figure imgf000256_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:
U6 is -C(R6b)2- or -O-; each R3a, R3b, R3c, R3d, R3e, R6a, and R6b is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) C(O)R1a, C(O)OR1a, C(O)NR1bR1c, C(O)SR1a, C(NR1 a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1 aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1 bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; each R6 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1aS(O)2R1d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; and b is an integer of 0, 1, 2, 3, 4, 5, or 6.
16. The compound of any one of claims 1 to 15, wherein U is -C(R4a)=.
17. The compound of any one of claims 1 to 15, wherein U is -N=.
18. The compound of any one of claims 1 to 17, wherein V is -C(R4a)=.
19. The compound of any one of claims 1 to 17, wherein V is -N=.
20. The compound of claim 14, having the structure of Formula (VIIIA):
Figure imgf000257_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
21. The compound of claim 14, having the structure of Formula (VIIIB):
Figure imgf000257_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
22. The compound of claim 15, having the structure of Formula (IXA):
Figure imgf000258_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
23. The compound of claim 15 or 22, having the structure of Formula (XA):
Figure imgf000258_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
24. The compound of claim 15 or 22, having the structure of Formula (XIA):
Figure imgf000258_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
25. The compound of claim 15, having the structure of Formula (IXB):
Figure imgf000259_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
26. The compound of claim 15 or 25, having the structure of Formula (XB):
Figure imgf000259_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
27. The compound of claim 15 or 25, having the structure of Formula (XIB):
Figure imgf000259_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
28. The compound of any one of claims 15 to 19 and 22 to 27, wherein R6a is hydrogen or halo.
29. The compound of any one of claims 15 to 19 and 22 to 28, wherein R6a is hydrogen or fluoro.
30. The compound of any one of claims 15 to 19 and 22 to 29, wherein U6 is
-C(H2)- or -O-.
31. The compound of any one of claims 15 to 19 and 22 to 30, wherein b is an integer of 0.
32. The compound of any one of claims 1 to 31, wherein Re is a moiety of a cereblon (CRBN) E3 ligand.
33. The compound of any one of claims 1 to 32, wherein Re is a moiety having the structure of Formula (El):
Figure imgf000260_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein:
Ae is a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
Z is -CH2- or -C(O)-; one of Z1, Z2, Z3, and Z4 is -C= and the remaining three of Z1, Z2, Z3, and Z4 are each independently -C(Re4)=; or Z1 is a bond; one of Z2, Z3, and Z4 is -C=, and the remaining two of Z2, Z3, and Z4 are each independently -C(Re4)= or -S-; Re1 is hydrogen, deuterium, halo, or Ci-6 alkyl;
Re2 is hydrogen or Ci-6 alkyl; each Rc3 is independently (i) deuterium, cyano, halo, or nitro; (ii) Ci-6 alkyl, Ci-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, NR1 aC(S)NR1bR1c, NR1aS(O)R1d, NR1 aS(O)2R1d, NR1 aS(O)NR1bR1c, NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; each Re4 is independently hydrogen or Re3; and m is an integer of 0, 1, or 2; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclyl ene is optionally substituted with one or more substituents Q.
34. The compound of claim 33, wherein Re is a moiety having the structure of Formula (EIV):
Figure imgf000261_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
35. The compound of claim 33, wherein Re is a moiety having the structure of Formula (EV):
Figure imgf000261_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
36. The compound of any one of claims 33 to 35, wherein Z is -CH2-.
37. The compound of any one of claims 33 to 35, wherein Z is -C(O)-.
38. The compound of any one of claims 33 to 37, wherein m is an integer of 1.
39. The compound of claim 33, having the structure of Formula (XIIA):
Figure imgf000262_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
40. The compound of claim 33, having the structure of Formula (XIIIA):
Figure imgf000262_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
41. The compound of claim 33, having the structure of Formula (XIIB):
Figure imgf000263_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
42. The compound of claim 33, having the structure of Formula (XIIIB):
Figure imgf000263_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
43. The compound of any one of claims 1 to 32, wherein Re is a moiety having the structure of Formula (EXV):
Figure imgf000263_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein: Ae is a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
Xe is C(Re1) or N;
Re1 is hydrogen, deuterium, halo, or C1-6 alkyl;
Re2 is hydrogen or C1-6 alkyl; each Re3 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1 bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1bR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a,
OS(O)2R1a, OS(O)NR1bR1c, OS(O)2NR1bR1c, NR1bR1c, NR1 aC(O)R1d, NR1 aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR1bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1d, -NR1 aS(O)NR1 bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c;
Re5 is (i) hydrogen; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR’a, -C(NR1 a)NR1bR1 c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1 c, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; m is an integer of 0, 1, or 2; and n is an integer of 0, 1, 2, or 3; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.
44. The compound of claim 43, wherein Re is a moiety having the structure of Formula (EXVII):
Figure imgf000264_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
45. The compound of claim 43, wherein Re is a moiety having the structure of Formula (EXVIII):
(EXVIII)
Figure imgf000265_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
46. The compound of claim 43, wherein Re is a moiety having the structure of Formula (EXX):
Figure imgf000265_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
47. The compound of claim 43, wherein Re is a moiety having the structure of Formula (EXXI):
Figure imgf000265_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
48. The compound of any one of claims 43 to 47, wherein m is an integer of 1.
49. The compound of any one of claims 43 to 48, wherein n is an integer of 0 or 1.
50. The compound of any one of claims 43 to 49, wherein Re3 is halo.
51. The compound of any one of claims 43 to 50, wherein Re3 is fluoro or chloro.
52. The compound of claim 43, wherein the compound is a compound of Formula
(XIV A):
Figure imgf000266_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein Re4 is hydrogen or Re3.
53. The compound of claim 43, wherein the compound is a compound of Formula
(XIVB):
Figure imgf000266_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein Re4 is hydrogen or Re3.
54. The compound of any one of claims 43, 52, and 53, wherein Xe is C(Re1).
55. The compound of claim 52, wherein the compound is a compound of Formula
(XVIA):
Figure imgf000267_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
56. The compound of claim 52, wherein the compound is a compound of Formula (XVII A):
Figure imgf000267_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
57. The compound of claim 52, wherein the compound is a compound of Formula (XVIII A):
Figure imgf000267_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
58. The compound of claim 53, wherein the compound is a compound of Formula
(XVIB):
Figure imgf000268_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
59. The compound of claim 53, wherein the compound is a compound of Formula (XVIIB):
Figure imgf000268_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
60. The compound of claim 53, wherein the compound is a compound of Formula (XVIIIB):
Figure imgf000269_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
61. The compound of claim 43, wherein the compound is a compound of Formula
(XIX A):
Figure imgf000269_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein Re4 is hydrogen or Re3.
62. The compound of claim 43, wherein the compound is a compound of Formula
(XIXB):
Figure imgf000270_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein Re4 is hydrogen or Re3.
63. The compound of claim 61 or 62, wherein Xe is C(Re1).
64. The compound of claim 61, wherein the compound is a compound of Formula
(XXIA):
Figure imgf000270_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
65. The compound of claim 61, wherein the compound is a compound of Formula (XXII A):
Figure imgf000271_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
66. The compound of claim 61, wherein the compound is a compound of Formula (XXIIIA):
Figure imgf000271_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
67. The compound of claim 62, wherein the compound is a compound of Formula
(XXIB):
Figure imgf000271_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
68. The compound of claim 62, wherein the compound is a compound of Formula
(XXIIB):
Figure imgf000272_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
69. The compound of claim 62, wherein the compound is a compound of Formula (XXIIIB):
Figure imgf000272_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
70. The compound of any one of claims 43 to 69, wherein Re5 is Ci-6 alkyl, optionally substituted with one or more substituents Q.
71 . The compound of any one of claims 43 to 70, wherein Re5 is methyl.
72. The compound of any one of claims 1 to 32, wherein Re is a moiety having the structure of Formula (EXXII):
Figure imgf000273_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; wherein:
Ae is a bond, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene;
Xe is C(Re1) or N;
Re1 is hydrogen, deuterium, halo, or C1-6 alkyl;
Re2 is hydrogen or C1-6 alkyl; each Re3 is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6 alkyl, C1-6 heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1a, -C(O)OR1a, -C(O)NR1bR1c, -C(O)SR1a, -C(NR1a)NR1bR1c, -C(S)R1a, -C(S)OR1a, -C(S)NR1bR1c, -OR1a, -OC(O)R1a, -OC(O)OR1a, -OC(O)NR1hR1c, -OC(O)SR1a, -OC(NR1 a)NR1bR1c, -OC(S)R1a, -OC(S)OR1a, -OC(S)NR1bR1c, -OS(O)R1a, -OS(O)2R1a, -OS(O)NR1bR1c, -OS(O)2NR1bR1c, -NR1bR1c, -NR1 aC(O)R1d, -NR1aC(O)OR1d, -NR1 aC(O)NR1bR1c, -NR1 aC(O)SR1d, -NR1 aC(NR1d)NR1bR1c, -NR1aC(S)R1d, -NR1 aC(S)OR1d, -NR1 aC(S)NR’bR1c, -NR1aS(O)R1d, -NR1 aS(O)2R1 d, -NR1 aS(O)NR1bR1c, -NR1aS(O)2NR1bR1c, -SR1a, -S(O)R1a, -S(O)2R1a, -S(O)NR1bR1c, or -S(O)2NR1bR1c; m is an integer of 0, 1, or 2; and n is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.
73. The compound of claim 72, wherein Re is a moiety having the structure of Formula (EXXIV): (EXXIV)
Figure imgf000274_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
74. The compound of claim 72, wherein Re is a moiety having the structure of
Formula (EXXV):
Figure imgf000274_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
75. The compound of claim 72, wherein Re is a moiety having the structure of Formula (EXXVII):
(EXXVII)
Figure imgf000274_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
76. The compound of claim 72, wherein Re is a moiety having the structure of Formula (EXXVIII):
(EXXVIII)
Figure imgf000274_0004
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.
77. The compound of any one of claims 72 to 76, wherein m is an integer of 1 .
78. The compound of claim 72, having the structure of Formula (XXIVA):
Figure imgf000275_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
79. The compound of claim 72, having the structure of Formula (XXIVB):
Figure imgf000275_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
80. The compound of any one of claims 72, 78, and 79, wherein Xe is C(Re1).
81 . The compound of claim 78, having the structure of Formula (XXVIA):
Figure imgf000276_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
82. The compound of claim 78, having the structure of Formula (XXVIIA):
Figure imgf000276_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
83. The compound of claim 78, having the structure of Formula (XXVIIIA):
Figure imgf000276_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
84. The compound of claim 79, having the structure of Formula (XXVIB):
Figure imgf000277_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
85. The compound of claim 79, having the structure of Formula (XXVIIB):
Figure imgf000277_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
86. The compound of claim 79, having the structure of Formula (XXVIIIB):
Figure imgf000277_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
87. The compound of claim 72, having the structure of Formula (XXIXA):
Figure imgf000278_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
88. The compound of claim 72, having the structure of Formula (XXIXB):
Figure imgf000278_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
89. The compound of claim 87 or 88, wherein Xe is C(Re1).
90. The compound of claim 87, having the structure of Formula (XXXIA):
Figure imgf000279_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
91. The compound of claim 87, having the structure of Formula (XXXIIA):
Figure imgf000279_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
92. The compound of claim 87, having the structure of Formula (XXXIIIA):
Figure imgf000279_0003
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
93. The compound of claim 88, having the structure of Formula (XXXIB):
Figure imgf000280_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
94. The compound of claim 88, having the structure of Formula (XXXIIB):
Figure imgf000280_0002
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
95. The compound of claim 88, having the structure of Formula (XXXIIIB):
Figure imgf000281_0001
or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
96. The compound of any one of claims 72 to 95, wherein n is an integer of 0, 1, or 3.
97. The compound of any one of claims 72 to 96, wherein each Re3 is independently (i) halo; or (ii) Ci-6 alkyl, Ci-6 heteroalkyl, or C3-7 cycloalkyl, each optionally substituted with one or more substituents Q.
98. The compound of any one of claims 72 to 97, wherein each Re3 is independently fluoro, chloro, methyl, difluoromethyl, trifluoromethyl, or cyclopropyl.
99. The compound of any one of claims 1 to 98, wherein R1 is hydrogen.
100. The compound of any one of claims 1 to 99, wherein R2a is C1-6 alkyl, optionally substituted with one or more substituents Q.
101. The compound of any one of claims 1 to 100, wherein R2a is methyl.
102. The compound of any one of claims 14 to 101, wherein R3a is (i) hydrogen, cyano, halo, or nitro; (ii) C1-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.
103. The compound of any one of claims 14 to 102, wherein R3a is hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, tri fluoromethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl.
104. The compound of any one of claims 14 to 103, wherein R3a is hydrogen, fluoro, or methyl.
105. The compound of any one of claims 14 to 104, wherein R3b is (i) hydrogen, cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.
106. The compound of any one of claims 14 to 105, wherein R3b is hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluorom ethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.
107. The compound of any one of claims 14 to 106, wherein R3b is hydrogen, cyano, fluoro, difluoromethyl, trifluoromethyl, or amino.
108. The compound of any one of claims 14 to 107, wherein R3c is (i) hydrogen, cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.
109. The compound of any one of claims 14 to 108, wherein R3c is hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluorom ethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.
110. The compound of any one of claims 14 to 109, wherein R3c is hydrogen.
111. The compound of any one of claims 14 to 110, wherein R3d is (i) hydrogen, cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.
112. The compound of any one of claims 14 to 1 11 , wherein R3d is hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluorom ethyl, trifluorom ethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methyl sulfonyl.
113. The compound of any one of claims 14 to 112, wherein R3d is hydrogen.
114. The compound of any one of claims 14 to 113, wherein R3e is (i) hydrogen, cyano, halo, or nitro; (ii) Ci-6 alkyl or C6-14 aryl, each optionally substituted with one or more substituents Q; or (iii) -OR1a, -NR1bR1c, or -S(O)2R1a.
115. The compound of any one of claims 14 to 114, wherein R3e is hydrogen, cyano, fluoro, chloro, bromo, nitro, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1- cyano- 1 , 1 -difluoromethyl, 1 , 1 -difluoro-2-hydroxy ethyl, 1 , 1 -difluoro-2-hydroxy-2-methylpropyl, methylaminomethyl, 2-aminomethylphenyl, 2-(2-aminoethyl)phenyl, 2-methylaminomethyl- phenyl, 2-dimethylaminomethylphenyl, hydroxyl, methoxy, amino, or methylsulfonyl.
116. The compound of any one of claims 14 to 115, wherein R3e is hydrogen.
117. The compound of any one of claims 1 to 116, wherein R4a is Ci-6 alkyl, optionally substituted with one or more substituents Q.
118. The compound of any one of claims 1 to 117, wherein R4a is methyl.
119. The compound of any one of claims 33 to 118, wherein Ae is heterocyclylene, optionally substituted with one or more substituents Q.
120. The compound of any one of claims 33 to 119, wherein Ae is monocyclic heterocyclylene, optionally substituted with one or more substituents Q.
121. The compound of any one of claims 33 to 119, wherein Ae is bicyclic heterocyclylene, optionally substituted with one or more substituents Q.
122. The compound of any one of claims 33 to 119, wherein Ae is piperidindiyl, piperazindiyl, or 8-azabicyclo[3.2.1]octandiyl, each optionally substituted with one or more substituents Q.
123. The compound of any one of claims 33 to 119 and 122, wherein Ae is piperidin- 1,4-diyl, piperazin- 1,4-diyl, or 8-azabicyclo[3.2.1]octan-3,8-diyl, each optionally substituted with one or more substituents Q.
124. The compound of any one of claims 33 to 118, wherein Ae is a bond,
125. The compound of any one of claims 33 to 45, 48 to 56, 58, 59, 61 to 65, 67, 68, 70 to 74, 77 to 82, 84, 85, 87 to 91, 93, 94, and 96 to 124, wherein Re1 is Ci-6 alkyl, optionally substituted with one or more substituents Q.
126. The compound of any one of claims 33 to 45, 48 to 56, 58, 59, 61 to 65, 67, 68, 70 to 74, 77 to 82, 84, 85, 87 to 91, 93, 94, and 96 to 125, wherein Re1 is methyl.
127. The compound of any one of claims 33 to 45, 48 to 56, 58, 59, 61 to 65, 67, 68, 70 to 74, 77 to 82, 84, 85, 87 to 91, 93, 94, and 96 to 124, wherein Re1 is hydrogen.
128. The compound of any one of claims 33 to 127, wherein Re2 is Ci-6 alkyl, optionally substituted with one or more substituents Q.
129. The compound of any one of claims 33 to 128, wherein Re2 is (pivaloyloxy)- methyl, valyloxymethyl, or ((di-/er/-butoxyphosphoryl)oxy)methyl.
130. The compound of any one of claims 33 to 127, wherein Re2 is hydrogen.
131. The compound of any one of claims 34 to 42, 52 to 71, and 99 to 130, wherein Re4 is halo.
132. The compound of any one of claims 34 to 42, 52 to 71, and 99 to 131, wherein Re4 is fluoro or chloro.
133. The compound of any one of claims 34 to 42, 52 to 71, and 99 to 132, wherein Re4 is fluoro.
134. The compound of any one of claims 34 to 42, 52 to 71 , and 99 to 130, wherein Re4 is hydrogen.
135. The compound of any one of claims 20, 21, and 32 to 134, wherein U5 is -C(R5)=.
136. The compound of any one of claims 20, 21, and 32 to 134, wherein U5 is -N=.
137. The compound of any one of claims 20, 21, and 32 to 136, wherein V5 is -C(R .
138. The compound of any one of claims 20, 21, and 32 to 136, wherein
Figure imgf000285_0001
is -N=.
139. The compound of any one of claims 20, 21, and 32 to 138, wherein X5 is
-C(R5)=.
140. The compound of any one of claims 20, 21, and 32 to 138, wherein X5 is -N=.
141. The compound of any one of claims 20, 21, and 32 to 140, wherein Z5 is -C(R5)=.
142. The compound of any one of claims 20, 21, and 32 to 140, wherein Z5 is -N=.
143. The compound of any one of claims 20, 21, and 32 to 134, wherein U5, V5, X5, and Z’ are each independently -C(R5)=.
144. The compound of any one of claims 20, 21, and 32 to 134, wherein U5 is -N=; and V5, X5, and Z5 are each independently -C(R5)=.
145. The compound of any one of claims 20, 21, and 32 to 134, wherein U5, X5, and Z5 are each independently -C(R5)=; and V5 is -N=.
146. The compound of any one of claims 20, 21, and 32 to 134, wherein U5, V5, and Z5 are each independently -C(R’)=; and X5 is -N=.
147. The compound of any one of claims 20, 21, and 32 to 134, wherein U5, V5, and X5 are each independently -C(R3)=; and Z5 is -N=.
148. The compound of any one of claims 135 and 137 to 147, wherein each R? is independently (i) hydrogen or halo; or (ii) Ci-6 alkyl, optionally substituted with one or more substituents Q.
149. The compound of any one of claims 135 and 137 to 148, wherein each R5 is independently hydrogen, fluoro, chloro, or methyl.
150. The compound of any one of claims 1 to 149, wherein L has the structure of:
-Zk-(Rk-Zk)z-; wherein: each Rk is independently Ci-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-10 cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents Q; each Zk is independently a bond, -C(O)-, -C(O)O- -C(O)NR1 b- -C(O)S- -C(NR1a)NR1b-, -C(S)-, -C(S)O- -C(S)NR1b-, -O-, -OC(O)O-, -OC(O)NR1b- -OC(O)S- -OC(NR1a)NR1b-, -OC(S)O-, -OC(S)NR1b-, -OS(O)-, -OS(O)2- -OS(O)NR1 b- -OS(O)2NR1b- -NR1b- -NR1aC(O)NR1b-, -NR1aC(O)S-, -NR1aC(NR1d)NR1b- -NR1 aC(S)NR1b-, -NR1aS(O)NR1b-, -NR1aS(O)2NR1b-, -S-, -S(O)-, -S(O)2-, -S(O)NR1b-, or -S(O)2NR1b-; where each R1a, Rlb, and R1d is as defined herein; and z is an integer of 0, 1, 2, 3, 4, or 5.
151. The compound of any one of claims 1 to 150, wherein L is C1-6 alkylene or C7-14 arylene, each optionally substituted with one or more substituents Q.
152. The compound of any one of claims 1 to 151, wherein L is methanediyl, ethane- 1,2-diyl, phen-l,3-diylmethandiyl, or -C(O)-.
153. The compound of any one of claims 1 to 152, wherein L is methanediyl.
154. The compound of any one of claims 1 to 153, wherein a is an integer of 0.
155. A compound of :
3 -(5 -( 1 -( 5 - (4- ( ((R)- 1 -(3 -(difluorom ethyl )-2-fluorophenyl )ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A001;
3 - (5 - ( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3, 4- J]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione A002;
3 -(5 -( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2,6- dione A003;
3 -(5-( 1 -(5-(4-(( (R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione A004;
3 -(5-( 1 -((5-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)pyridin-3-yl)methyl)piperidin-4-yl)-6-fluoro-l-oxo- isoindolin-2-yl)piperidine-2, 6-dione A005;
(R)-3 -(6-( 1 -(3 -(4 - (((R) - 1 -(3 -(difluoro-methyl)-2-fluorophenyl)ethyl )amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-5-fluoro-l -methyl- 1H-indazol-3-yl)- 3 -methylpiperidine-2, 6-dione A051 ; (R)-1-(6-(1-(5-(1-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-1H-indazol-3-yl)dihydro- pyrimidine-2, 4(1H, 3H)-dione A061; (R)-1-(6-(1-(5-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorophenethyl)piperidin-4-yl)-l -methyl- 1H-indazol-3-yl)- dihydropyrimidine-2,4( 1H,3H)-dione A062; (R)-1-(6-(1-(5-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-5-fluoro-l -methyl- 1H-indazol-3- yl)dihydropyrimidine-2,4(1H, 3H)-dione A063; (R)-1-(6-(1-(3-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-5-fluoro-l-m ethyl- 1H-indazol-3-yl)dihydro- pyrimidine-2,4(1H,3H)-dione A064; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione A101; 3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2,6- dione A102; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4- ]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3 -methyl- piperidine-2, 6-dione A103; (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3-ni ethylpiperidine- 2,6-dione A104; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)- 3-methylpiperidine-2, 6-dione A105;
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione A106;
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3-methyl- piperidine-2, 6-dione A107; R)-3 -(4-( 1 -(5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-r/]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione A108;
(R)-3 -(3 -cy clopropy l-4-( 1 - ( 5 -(4 - (((R) - 1 -(3 -(difluoromethy l)-2-fluorophenyl)- ethyl)amino)-2-methylpyrido[3,4-7]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A109; (R)-3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-7]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3 -methyl- piperidine-2, 6-dione A110;
(R)-3 -(3 -cy clopropy l-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny 1)- ethyl)amino)-2-methylpyrido[3,4-7]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A1li;
3-(4-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-r/]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione A112; (R)-3-(3-chloro-4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione A113;
(R)-3 -(3 -chloro-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluorom ethyl)-2-fluorophenyl)ethyl)- amino)-2-methylpyrido[3,4--d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione A114;
(R)-3 -(4-( 1 -((5 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethy l)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-l -methyl -2-oxo- 1,2-dihydropyri din-3 -yl)m ethyl)piperidin- 4-yl)phenyl)-3-methylpiperidine-2, 6-dione A115;
(R)-3 -(3 -(difluoromethyl)-4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluorom ethyl)-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione A116;
(R)-3 -(3 -(difluoromethyl)-4-( 1 -(5 -(4-( ((R)- 1 -(3 -(difluorom ethyl )-2-fluoro- phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3 -methylpiperidine-2, 6-dione A117;
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluorom ethyl)-2-flu oropheny l)ethy l)amino)-2- methylpyrido[3,4-fi?]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione A118;
3-(4-(1-(3-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- di one A119;
3-(4-(1-(5-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl- pyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)- piperidine-2, 6-dione A120;
(R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2,3-difluorophenyl)-3-methyl- piperidine-2, 6-dione A121; (R)-3-(4-(l -(5 -(4-(((R)-l -(3 -(difluorom ethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methyl-piperidine-2, 6-dione A122; (R)-3-(4-(l -(((5)-1-(4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4-d]pyrimidin-6-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione A123; (R)-3 -(4-( 1 -(3 -(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- methylpyrido[3,4--d]pyrimidin-6-yl)benzyl)piperidin-4-yl)-2-fluoro-3-methylphenyl)-3-methyl- piperidine-2, 6-dione A124;
3-(5-(4-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B001;
3-(6-fluoro-5-(1-(3-(4-methyl-1-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine- 2,6-dione B002;
3-(5-(4-(3-(1-(((R)-1-(3-arnino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperazin-l-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B003;
3 -(5-( 1 -(5-(l -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3, 4-d]pyridazin-7-yl)-2 -fluorobenzyl )piperi din-4-yl)-6-fluoro- 1 -oxoisoindolin-2-yl)- piperidine-2, 6-dione B004;
3 -(5 -( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)- piperidine-2, 6-dione B005;
3 -(5 -( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl )-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-6-fluoro-l-oxoisoindolin-2- yl)piperidine-2, 6-dione B006;
3-(5-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione B007;
3-(l-methyl-6-(4-(3-(4-methyl-1-(((R)-1-(2-methyl-3-(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperazin-l-yl)-17/-indazol-3-yl)piperidine-2,6- dione B051;
3-((17?)-1-((7-(4-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-17/-indazol-6-yl)- piperidin-l -yl)methyl)phenyl)piperazin-l-yl)-4-methylpyrido[3,4-d ]pyridazin-l-yl)amino)ethyl)- 2-methylbenzonitrile B052;
3 -(( 1R)- 1 -((7-(3 -((4-(3 -(2,6-dioxopiperidin-3 -yl)- 1 -methyl- 1H-indazol-6-yl)- piperidin-l-yl)methyl)phenyl)-4-methylpyrido[3,4-d ]pyridazin-l-yl)amino)ethyl)-2-methyl- benzonitrile B053;
3 -( 1 -methy l-7-( 1 -(3 -(4-methyl- 1 - ( ((R)- 1 -(2-methyl-3 -(trifluoromethyl)phenyl)- ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-1H-indazol-3-yl)piperidine-2,6- dione B054;
3-(6-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-l -methyl- 1H-indazol-3-yl)piperidine-2, 6- dione B055;
3-((17?)-1-((7-(3-((4-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-17/-indazol-7-yl)- piperi din- l-yl)methyl)phenyl)-4-methylpyrido[3,4-7]pyridazin-l-yl)amino)ethyl)-2 -methylbenzonitrile B056;
3 -(7-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-17/-indazol-3-yl)- piperidine-2, 6-dione B057; (R)-3 -(6-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l-methyl-17/-indazol-3-yl)-3- methylpiperidine-2, 6-dione B058;
(R)- 1 -(6-( 1 -(5 -( 1 -(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-l -methyl- 1H-indazol-3- yl)dihydropyrimidine-2, 4(1H, 3H)-di one B091;
(R)- 1 -(6-( 1 -(5 -( 1 -(( 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)-amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorophenethyl)piperidin-4-yl)-l-methyl-1H-indazol-3- yl)-dihydropyrimidine-2,4(17f,3H)-dione B092;
3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B101;
3-(4-(1-(3-(l -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B102; 3-(4-(1-(3-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)phenethyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B103;
3 -(4-(4-(3 -( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4--d]pyridazin-7-yl)phenethyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B104;
3 -(4-(4-(3 -( 1 -(((R)- 1 -(3 -amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4- ]pyridazin-7-yl)benzyl)piperazin-l-yl)phenyl)piperidine-2, 6-dione B105;
3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -amino-5 -(trifluoromethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)- piperidine-2, 6-dione B106;
3-(4-(2-(5-(1-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-oxopyridin-l(27/)-yl)ethyl)phenyl)piperidine-2, 6-dione B107;
3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B108;
3-((17?)-1-((7-(3-((4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperidin-l-yl)methyl)- phenyl)-4-methylpyrido[3,4-t/]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile B109;
3 -(4-( 1 -(3 -(4-m ethyl- 1 -(((R)- 1 -(2-methyl-3 -(trifluoromethy l)pheny 1 ) ethyl ) - amino)pyrido[3,4- ]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 10;
3 -(4-( 1 -(2-(5-(l -(((R)- 1 -(3 -amino-5 -(trifluorom ethyl)phenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-oxopyridin-l(2H)-yl)ethyl)piperidin-4-yl)phenyl)- piperidine-2, 6-dione Bill;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-5-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B112;
3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-4-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 13;
3 - (4 - ( 1 -( 5 - ( 1 -(((R)- 1 -(3 -(difluorom ethyl )-2-fluorophenyl )ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 14;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 15;
3 -(4-( 1 -(3 -(1 -(((R)- 1 -(3 -(difluorom ethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-5-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B116;
3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 17;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3, 4- J]pyridazin-7-yl)-4-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 18;
3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-methylbenzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione Bl 19;
3 -(4-( 1 -(3 -(1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)phenethyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B120;
3 -(4-( 1 -(2-chl oro-5 -( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)- 4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2, 6-dione B121;
2-methyl-3-((R)-1-((4-methyl-7-(3-((4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)- phenyl)piperidin-l-yl)methyl)phenyl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile B122; (R)-3 -methyl-3 -(4-( 1 -(3-(4-methyl- 1 -(((R)- 1 -(2-methy 1-3 -(trifluoromethyl)- phenyl)ethyl)amino)pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)piperidine-2,6- dione B123;
2-methyl-3-((R)-1-((4-methyl-7-(3-((4-(4-((R)-3-methyl-2,6-dioxopiperidin-3-yl)- phenyl)piperidin-l-yl)methyl)phenyl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile B124; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-2, 6-dione B125; (R) - 3 -(4 - ( 1 - ( 5 -( 1 - (((R) - 1 -(3 -(difluoromethy l)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B126; (R)-3 -(4-(l -(5-( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B127; (R)-3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione B128; (R)-3-(4-(1-(2-fluoro-5-(1-(((R)-1-(3-fluoro-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)benzyl)pi peri din-4-yl)phenyl)-3-methylpiperidine-2, 6-dione B129;
3-(4-(1-(5-(l - ( ((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2,6- dione B130;
3 -(4-( 1 -( 5 -( 1 -(((R)- 1 -(3 -(difluorom ethyl )-2-fluorophenyl )ethyl)amino)-4-methyl- pyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)piperidine-2, 6-dione B131;
3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)- piperidine-2, 6-dione B132; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluorom ethyl)-2-flu orophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2,6-dione B133; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluorom ethyl)-2-flu oropheny l)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-5-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione B134; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluorom ethyl)-2-flu orophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-4-fluorobenzyl)piperidin-4-yl)phenyl)-3-methylpiperidine- 2, 6-dione B135; (R)-3 -(4-( 1 -(((R)-4-( 1 -(((R)- 1 -(3 -(difluorom ethyl)-2-fluorophenyl)ethy l)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)morpholin-2-yl)methyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B136; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-methylphenyl)-3-mefhylpiperidine- 2, 6-dione B137; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-methylphenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-mefhyl- piperidine-2, 6-dione B138; (R) - 3 -(4 - ( 1 - ( 5 -( 1 - (((R) - 1 -(3 -(difluorom ethy l)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B139;
(R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)-l,2,3,6-tetrahydropyridin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B140;
(R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)furan-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methyl- piperidine-2, 6-dione B141;
(37?) - 3 -(4-(8-(((R)-4-( 1 -(((R)- 1 -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 4-methylpyrido[3,4-d ]pyridazin-7-yl)morpholin-2-yl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-3- methylphenyl)-3-methylpiperidine-2, 6-dione B142;
(37?) - 3 -(4 - (8 - (5 - ( 1 -(((R) - 1 - (3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B143; (R) - 3 -( 4 - ( 1 - ( (5 - ( 1 - (((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl )amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)pyridin-3-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B144; (R) - 3 -(4 - ( 1 - ( 5 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fhiorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-(trifluorornethyl)phenyl)-3- methylpiperidine-2, 6-dione B145;
(R)-3 -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-(trifluoromethyl)phenyl)-3-methyl- piperidine-2, 6-dione B146; (R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d ]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3-methyl- piperidine-2, 6-dione B147; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoropheny l)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)-3- methylpiperidine-2, 6-dione B148; (R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)thiophen-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B149; (R)-3-(4-(l -(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)arnino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluorophenyl)-3-methyl- piperidine-2, 6-dione B150;
(R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluorophenyl)-3-methylpiperidine- 2,6-dione B151; (R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzoyl)piperidin-4-yl)phenyl)-3-methylpiperidine-
2.6-dione B152;
((R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluorornethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-methylphenyl)-3-methyl-
2.6-dioxopiperidin-l-yl)methyl pivalate B153;
3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-methylphenyl)piperidine-2, 6-dione B154; (R)-3 -(4-( 1 -((4-( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)pyridin-2-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3- methylpiperidine-2, 6-dione B155; (R)-3 -(3 -chloro-4-( 1 -(5-( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluorophenyl)ethyl)- amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B156; (R)-3-(3-chloro-4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methylpiperidine-
2.6-dione B157; (R)-3 -(3 -cy clopropyl-4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione B158;
(R)-3 -(3 -cy clopropyl-4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)- ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3-methyl- piperidine-2, 6-dione B159;
(R)-3 -(4-( 1 -(( (S)- 1 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)-3-fluoropiperidin-3-yl)methyl)piperidin-4-yl)-3-methyl- phenyl)-3-methylpiperidine-2, 6-dione B160;
(R)-3 -(4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3,5-difluorophenyl)-3- methylpiperidine-2, 6-dione B161;
(R)-3 -(4-( 1 -(3 -( 1 - (((R) - 1 -(3 -(difluoromethy l)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4--d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-2-methylphenyl)-3-methyl- piperidine-2, 6-dione B162;
(R)-3 -(3 -(difluoromethyl)-4-( 1 -(5 -( 1 -(((R)- 1 -(3 -(difluoromethy l)-2-fluoro- phenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)- phenyl)-3-methylpiperidine-2, 6-dione B163;
(R)-3 -(3 -(difluoromethyl)-4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluoro- phenyl)ethyl)amino)-4-methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)phenyl)-3- methylpiperidine-2, 6-dione B164;
(R)-3 -(4-( 1 -(3 -( 1 -(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4- methylpyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3,5-difluorophenyl)-3-methyl- piperidine-2, 6-dione B165;
3-(4-(1-(3-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)benzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine-2,6- dione B166;
3-(4-(1-(5-(1-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)-3-fluoro-5-methylphenyl)piperidine- 2,6-dione B167; (R)-1-(4-(1-(5-(1-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-4-methyl- pyrido[3,4-d]pyridazin-7-yl)-2-fluorobenzyl)piperidin-4-yl)phenyl)dihydropyrimidine- 2, 4( 1H,370-dione B201; (R)-3 -(4-( 1 -((6-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 1 - methylphthalazin-6-yl)pyri din-2 -yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C001; (R)-3 -(4-( 1 -((2-(4-(((R)- 1 -(3 -(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 1 - methylphthal azin-6-yl)pyri din-4-yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2, 6-dione C002; or (R)-3-(4-(l -((4-(4-(((R)-l -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-l - methylphthalazin-6-yl)pyri din-2 -yl)methyl)piperidin-4-yl)-3-methylphenyl)-3-methylpiperidine- 2,6-dione C003; or an enantiomer, a mixture of enantiomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
156. A pharmaceutical composition comprising the compound of any one of claims 1 to 155, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable excipient.
157. The pharmaceutical composition of claim 156, wherein the composition is in single dosage form.
158. The pharmaceutical composition of claim 156 or 157, wherein the composition is in an oral, parenteral, or intravenous dosage form.
159. The pharmaceutical composition of claim 158, wherein the composition is formulated in an oral dosage form.
160. The pharmaceutical composition of claim 159, wherein the oral dosage form is a tablet or capsule.
161. A method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a son of sevenless homolog 1 (S0S1) in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.
162. The method of claim 161, wherein the disorder, disease, or condition mediated by the S0S1 is a proliferative disease.
163. A method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a RAS in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.
164. The method of claim 163, wherein the disorder, disease, or condition mediated by the RAS is a proliferative disease.
165. A method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.
166. The method of claim 163, 164, or 165, wherein the proliferative disease is cancer.
167. The method of claim 166, wherein the cancer is colon cancer, colorectal cancer, lung cancer, or pancreatic cancer.
168. The method of claim 166 or 167, wherein the cancer is relapsed or refractory.
169. The method of any one of claims 166 to 168, wherein the cancer is metastatic.
170. The method of any one of claims 166 to 169, wherein the cancer is drug-resistant.
171. The method of any one of claims 161 to 170, wherein the subject is a human.
172. A method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.
173. The method of claim 172, wherein the cell is a cancerous cell.
174. A method of inducing degradation of an S0S1, comprising contacting the S0S1 with an effective amount of a compound of any one of claims 1 to 155 or a pharmaceutical composition of any one of claims 156 to 160.
PCT/US2024/042366 2023-08-16 2024-08-15 Sos1 protein degraders, pharmaceutical compositions, and therapeutic applications Pending WO2025038785A1 (en)

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